Vol. 31 (2026)



No.  01DOI: 10.1186/s11658-025-00827-2 Volume 31 (2026) - 30:01
Title LOSS OF ALPHA-KINASE 1 CONTRIBUTES TO THE FORMATION OF CONGENITAL CATARACTS IN MICE
Authors Hui-Shan Wang1†, Yu-Xin Yang1†, Shang-Shang Duan1†, Fang-Yi Long2, Ting Wu1, Nai-Hong Yan1, Xiao-Hong Li1* and Jun-Rong Du1*
Abstract Background: Alpha-kinase 1 (ALPK1), a cytosolic receptor involved in innate immune activation, promotes apical trafficking in epithelial cells. While its role in autoinflammatory disorders is known, its function in epithelial homeostasis remains unexplored. This study investigates ALPK1’s role in murine lens development and its pathological relevance to congenital cataracts (CCs).
Methods: We utilized ALPK1-deficient (ALPK1−/−) C57BL/6 mice and primary lens epithelial cells (LECs) with ALPK1 knockout (via lentiviral sgRNA) to analyze lens histo-morphological alterations and cellular and molecular pathologies, including apical protein transport and localization, endoplasmic reticulum (ER) stress, apoptosis, and LEC differentiation.
Results: We observed strong ALPK1 immunoreactivity in the LECs of C57BL/6 mice. ALPK1−/− mice developed CCs with combined Y-suture and cortical opacities, disrupted lens cell architecture, and vacuolar degeneration. Molecular dysregulation included reduced phosphorylation of myosin Ia, mislocalization of zonula occludens-1 (ZO-1) from apical tight junctions to cytoplasmic aggregates, upregulation of the endoplasmic reticulum (ER) stress marker C/EBP-homologous protein (CHOP), increased apoptosis (evidenced by TUNEL-positive cells), and disorganized interlocking patterns in lens fiber cells. Lentiviral ALPK1 re-expression in ALPK1−/− mice significantly restored lens transparency and ZO-1 apical localization, reduced CHOP expression, and suppressed apoptosis.
Conclusions: This study first demonstrates that ALPK1 is critical for maintaining LEC homeostasis by regulating myosin Ia phosphorylation-dependent apical trafficking and tight junction integrity. ALPK1 deficiency disrupts these processes, leading to loss of apical polarity, ER stress-induced apoptosis, and ultimately CC formation.
Keywords ALPK1, Apical transport, Congenital cataracts, Lens epithelial cells, Myosin Ia
Address and Contact Information 1 West China School of Pharmacy, West China School of Public Health, Research Laboratory of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, Sichuan, China
2 Laboratory Medicine Center, Sichuan Provincial Maternity and Child Health Care Hospital, Chengdu 610032, Sichuan, China
*Corresponding author: Xiao-Hong Li li_xiaohong@scu.edu.cn Jun-Rong Du dujunrong@scu.edu.cn
† Hui-Shan Wang, Yu-Xin Yang and Shang-Shang Duan have contributed equally to this work.
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No.  03DOI: 10.1186/s11658-025-00831-6 Volume 31 (2026) - 30:03
Title TRIGEMINAL NERVE ROOT COMPRESSION INDUCED NEUROINFLAMMATORY RESPONSE PROMOTES MECHANICAL ALLODYNIA THROUGH THE CGRP/SP-Piezo2 AXIS VIA Ca2+ SIGNALING
Authors Xinyue Liao1†, Zhaoke Luo1†, Feng Huang1†, Yiqian Wang1, Zhangying Zeng1, Weihang Liao1, Yating Ou1, Xuemei Wu1, Feng Wang1,2* and Daoshu Luo1,2*
Abstract Trigeminal neuralgia (TN) is one of the most severe types of neuropathic pain, but its pathological mechanisms remain unknown. In this study, we identified a unique neuroinflammatory response induced by chronic compression of trigeminal root entry zone (TREZ) in a TN rat model, establishing a connection between ATP-driven intracellular pathways and Piezo2-mediated mechanotransduction. Piezo2, the pain-related neuropeptide calcitonin gene-related peptide (CGRP) receptor complex CRLR-RAMP1 and the neuropeptide substance-P (SP) receptor NK1R are co-expressed on rat Merkel cells. Protein kinase C (PKC) plays a crucial role in upregulating Piezo2 and CGRP/SP expression in both the trigeminal ganglion (TG) and whisker pad, thereby facilitating orofacial mechanical allodynia in TN rats. Furthermore, the inhibition of cAMP signaling in the whisker pads effectively alleviated mechanical allodynia, while Piezo2 knockdown in both the TG and whisker pads significantly reversed db cAMP-induced allodynia. In vitro studies demonstrated that extracellular ATP not only enhances CGRP and SP expression but also induces Piezo2 expression through Ca2+-dependent activation of ERK1/2 and p38 MAPK cascades, mediated by specific transcription factors. These findings reveal that peripheral sensitization in TN is mediated through a Ca2+-CGRP/SP-Piezo2 positive feedback loop, dependent on the neuroinflammatory response along the TG neuron–Merkel cell axis as a prerequisite condition. This discovery provides a novel insight into the pathogenesis of TN.
Keywords Piezo2, CGRP/SP, Neuroinflammation, Trigeminal neuralgia, Ca2+-PKC
Address and Contact Information 1 Laboratory of Clinical Applied Anatomy, School of Basic Medical Sciences, Key Laboratory of Brain Aging and Neurodegenerative Diseases of Fujian Province, Fujian Medical University, 350122 Fuzhou, China 2 Department of Human Anatomy, The School of Basic Medical Sciences, Fujian Medical University, No. 1 Xuefu North Road, University Town 350122, Fuzhou, China *Corresponding author: Feng Wang fjwf95168@163.com Daoshu Luo luods2004@fjmu.edu.cn † Xinyue Liao, Zhaoke Luo and Feng Huang contributed equally to this work.
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No.  04DOI: 10.1186/s11658-025-00816-5 Volume 31 (2026) - 30:04
Title tsRNA-3040b ACCUMULATES R-LOOP TO REGULATe Trim35 TRANSCRIPTION, WHICH LEADS TO DISORDERED GLYCOLYSIS AND PROMOTES PAECS PROLIFERATION
Authors Xu Wang1†, Songyue Li1†, Jianli Hou1, Shukun Cao2, Yibin Zhang1, Jingya Zhang1, Xinru Wang1, Xinyue Song3, Ya Xu3, Jing Qi1, Yan Xing1,4* and Xiaodong Zheng2,4*
Abstract Background: Hypoxia significantly influences the development of pulmonary hypertension (PH). However, the role of transfer RNA-derived small RNAs (tsRNAs) produced by nuclease cleavage on PH, particularly their impact on the proliferation of pulmonary artery endothelial cells (PAECs), remains unclear.
Methods: To detect tsRNA expression, panoramic RNA display by overcoming RNA modification aborted sequencing (PANDORA-seq) sequencing analysis and quantitative polymerase chain reaction (qPCR) were employed. The formation of R-loops between tsRNA and genomic DNA was confirmed through chromatin immunoprecipitation followed by polymerase chain reaction (ChIP-PCR) and Dot-blot analyses. Mouse PAECs and lung tissue were manipulated to either overexpress or inhibit tsRNA-3040b, followed by assessments of cell proliferation, RT-qPCR, and enzyme activity assays on three key glycolytic rate-limiting enzymes. Molecular docking, immunofluorescence and endogenous coprecipitation were used to demonstrate the colocalization of Trim35 and Wnt3a.
Results: The expression of tsRNA-Asp-GTC-3040b (termed tsRNA-3040b) was significantly increased in the lung tissue of a hypoxia-induced PH mouse model. By integrating database prediction with RNA sequencing, Trim35 was identified as a downstream target of tsRNA-3040b. ChIP-PCR and Dot-blot analyses using S9.6 indicated that tsRNA-3040b promoted R-loops in the genomic DNA of Trim35, thus inhibiting its transcription. Further investigation revealed that the Trim35 affected glucose metabolism levels through ubiquitinated substrate Wnt3a. Ultimately, it was elucidated that the tsRNA-3040b–Trim35–Wnt3a–glucose metabolism signaling pathway exacerbated the progression of PH.
Conclusions: This study highlights the role of tsRNA-3040b in promoting PH by influencing glucose metabolism processes. These results offer a new approach to treating PH and suggest that tsRNA-3040b could serve as a potential target for diagnosing PH and related conditions.
Keywords Pulmonary hypertension, Glucose metabolism reprogramming, tRNA-derived small RNAs, R-loops, Trim35, Wnt3A, Cell proliferation
Address and Contact Information 1 Department of Pharmacology, Harbin Medical University-Daqing, Daqing 163319, Heilongjiang, People’s Republic of China
2 Department of Medical Genetics, Harbin Medical University-Daqing, Daqing 163319, Heilongjiang, People’s Republic of China
3 Central Laboratory, Harbin Medical University-Daqing, Daqing 163319, Heilongjiang, People’s Republic of China
4 Engineering Technology Research Center for Precision Diagnosis and Treatment of Frigid Zone-Related Diseases in Heilongjiang Province, Daqing, Heilongjiang 163319, People’s Republic of China
*Corresponding author: Yan Xing xingyan@hmudq.edu.cn Xiaodong Zheng zhengxiaodong@hmudq.edu.cn
† Xu Wang and Songyue Li contributed equally to this work.
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No.  06DOI: 10.1186/s11658-025-00835-2 Volume 31 (2026) - 30:06
Title A NOVEL tRF-Gly IS ASSOCIATED WITH OBESITY DEVELOPMENT THROUGH POST-TRANSCRIPTIONAL REGULATION OF LIPID METABOLISM
Authors Yuhang Lei1,2,3†, Mailin Gan1,2,3†, Kai Wang1,2,3†, Tianci Liao1,2,3, Yiting Yang1,2,3, Xue Zhao1,2,4, Xin Zhang1,2,3, Dujun Chen1,2,3, Xinyi Wang1,2,3, Jianfeng Ma1,2,3, Lili Niu1,2,3, Ye Zhao1,2,3, Lei Chen1,2,3, Xiaofeng Zhou1,2,3, Yan Wang1,2,3, Mingzhou Li1,2,3, Li Zhu1,2,3* and Linyuan Shen1,2,3*
Abstract Background: Obesity, characterized by excessive fat accumulation, represents a global health crisis closely linked to metabolic disorders such as type 2 diabetes, hypertension, and atherosclerosis. tRNA-derived small RNAs (tsRNAs) have recently emerged as important epigenetic regulators, yet their roles in fat deposition remain poorly characterized. This study aims to identify tsRNAs that influence fat accumulation and to elucidate their molecular mechanisms, with a focus on tRF‑Gly‑GCC‑037 (tRF‑Gly) as a candidate regulator of adipocyte differentiation.
Methods: Visceral adipose tissue was collected from obese and lean pigs for comprehensive tRF and tiRNA sequencing. Differential expression analysis identified tRF‑Gly as a highly abundant candidate in obese samples. Functional assays in 3T3‑L1 preadipocytes included both overexpression and knockdown of tRF‑Gly, followed by lipid accumulation measurements and assessment of key adipogenic markers (CEBPα and PPARγ) by quantitative real-time PCR (qRT‑PCR) and western blot. Mechanistically, dual‑luciferase reporter assays, RNA immunoprecipitation (RIP), and nuclear–cytoplasmic protein fractionation were performed to examine how tRF‑Gly modulates the RAC1/JNK2/β‑catenin signaling axis.
Results: tRF‑Gly was significantly upregulated in visceral adipose tissue from obese pigs and ranked among the most abundant tsRNAs. Overexpression of tRF‑Gly in 3T3‑L1 cells and in C57BL/6 mice promoted lipid accumulation and increased CEBPα and PPARγ expression, whereas tRF‑Gly knockdown reduced lipid deposition. Mechanistically, tRF-Gly was suggested to bind RAC1 mRNA with AGO3 involvement, leading to RAC1 silencing. Consistently, RAC1 knockdown phenocopied the adipogenic effects of tRF-Gly, whereas RAC1 overexpression reversed these effects. Furthermore, RAC1 deficiency disrupted the RAC1/JNK2/β‑catenin complex, impaired β‑catenin nuclear translocation, and suppressed Wnt/β‑catenin signaling.
Conclusions: Our findings demonstrate that tRF‑Gly functions as a key regulator of fat accumulation. By silencing RAC1 via AGO3, tRF‑Gly disrupts RAC1/JNK2/β‑catenin complex assembly, prevents β‑catenin nuclear translocation, and downregulates Wnt/β‑catenin signaling, thereby promoting lipid deposition. This study uncovers a novel epigenetic mechanism by which tRF‑Gly controls fat accumulation and suggests that targeting tRF‑Gly may represent a therapeutic strategy for obesity and related metabolic disorders.
Keywords tRF-Gly, RAC1, RAC1/JNK2/β-catenin transport complex, Wnt/β-catenin signaling pathway, Fat deposition
Address and Contact Information 1 Farm Animal Genetic Resources Exploration and Innovation Key Laboratory of Sichuan Province, Sichuan Agricultural University, Chengdu 611130, China
2 State Key Laboratory of Swine and Poultry Breeding Industry, Sichuan Agricultural University, Chengdu 611130, China
3 Key Laboratory of Livestock and Poultry Multi-Omics, Ministry of Agriculture and Rural Affairs, College of Animal and Technology, Sichuan Agricultural University, Chengdu 611130, China
4 Animal Disease Prevention and Green Development Key Laboratory of Sichuan Province, College of Life Sciences, Sichuan University, 610065 Chengdu, China
*Corresponding author: Li Zhu zhuli@sicau.edu.cn Linyuan Shen shenlinyuan@sicau.edu.cn
† Yuhang Lei, Mailin Gan and Kai Wang have contributed equally to this work.
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No.  07DOI: 10.1186/s11658-025-00832-5 Volume 31 (2026) - 30:07
Title CDCP1 ALLOSTERICALLY REGULATES THE AMPK α1 SUBUNIT TO ENHANCE FATTY ACID OXIDATION IN OSTEOBLASTS
Authors Xiang Li1,2†, Weichun Zhu3,4†, Jinlong Ma1,2, Zhenqian Sun1,2, Limin Wang5, Guangjun Jiao1,2*† and Yunzhen Chen1,2*†
Abstract Background: Lipid metabolism disorders in osteoblasts may lead to osteoporosis. CUB domain-containing protein 1 (CDCP1) is associated with various intracellular signaling pathways. We investigated how CDCP1 regulates lipid metabolism and osteoblast function.
Methods: This study utilized gene overexpression (via lentivirus) and loss-of-function (CRISPR/Cas9-mediated knockout) techniques to investigate the involvement of CDCP1 in lipid metabolism and osteogenesis. Transcriptomic and metabolomic analyses were performed to examine the mechanism of action of CDCP1. Furthermore, proximity ligation assays, GST pull-down, and molecular docking were employed to identify the interaction between CDCP1 and AMP-activated protein kinase (AMPK).
Results: CDCP1 alleviated bone loss in mice. In vitro, CDCP1 promoted the phosphorylation of AMPK. Phosphorylated AMPK can enhance the activity of carnitine palmitoyltransferase, leading to increased fatty acid oxidation and promoting osteogenesis. Mechanistically, CDCP1 prevents the formation of the autoinhibitory conformation of the autoinhibitory domain by binding to the α3 helix, thereby protecting AMPK phosphorylation from self-inhibition.
Conclusions: Our research revealed a new molecular mechanism linking CDCP1 and allosteric control of AMPK. These findings reveal for the first time the mechanism by which CDCP1 affects osteogenesis through lipid metabolism regulation, suggesting its potential as a therapeutic target for osteoporosis.
Keywords CDCP1, AMPK, Allosteric control, Fatty acid oxidation, Osteoblastic function
Address and Contact Information 1 Department of Orthopedics, Qilu Hospital of Shandong University, No.107, Wenhuaxi Road, Lixia District, Jinan 250000, China
2 The First Clinical College of Cheeloo College of Medicine, Shandong University, Jinan, Shandong, China
3 State Key Laboratory for Innovation and Transformation of Luobing Theory, Key Laboratory of Cardiovascular Remodeling and Function Research of MOE, NHC, CAMS and Shandong Province, Jinan, Shandong, China
4 Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, China
5 Department of Human Anatomy, Binzhou Medical University, Yantai, Shandong, China
*Corresponding author: Guangjun Jiao jiaoguangjun@sdu.edu.cn Yunzhen Chen qilucyz@yeah.net † Guangjun Jiao and Yunzhen Chen have contributed equally as corresponding authors. † Xiang Li and Weichun Zhu have contributed equally as first authors.
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No.  14DOI: 10.1186/s11658-025-00840-5 Volume 31 (2026) - 30:14
Title THE CANCER-TESTIS lncRNA LINC01940 PROMOTES GASTRIC CANCER MALIGNANT PROGRESSION AND CHEMORESISTANCE BY ENHANCING RIBOSOME BIOGENESIS VIA TAF15-MEDIATED NOL11 SUMOYLATION
Authors Weijie Zang1,2,3, Debiao Fan1,2,3, Zhuang Lu1,2,3,5, Xian Gao1,2,3, Danjie Xing1,2,3,6, Guangze Zhang1,2,3, Lei Liu2,4, Jianfeng Yi1,2,3, Junjie Chen2,3*, Yilin Hu1,2,3* and Wanjiang Xue1,2,3*
Abstract Background: Aberrant ribosome biogenesis promotes gastric cancer (GC) progression and contributes to chemoresistance by sustaining protein synthesis, upon which GC cell survival depends. However, the regulatory role of cancer-testis-associated long noncoding RNAs (CT-lncRNAs) in modulating ribosome biogenesis in GC remains largely unexplored.
Methods: First, we performed a screening of lncRNAs and identified CT-lncRNA LINC01940 on the basis of integrated expression and survival analyses using The Cancer Genome Atlas (TCGA) data. Subsequently, the impact of LINC01940 on GC progression and chemosensitivity was evaluated using in vitro cell functional assays, patient-derived organoid models, and in vivo subcutaneous tumor xenograft experiments. To further elucidate the underlying mechanisms, we employed a comprehensive approach combining bioinformatics analyses, RNA sequencing, fluorescence in situ hybridization, translation assays, ribosomal DNA (rDNA) transcription assays, methylated RNA immunoprecipitation, co-immunoprecipitation mass spectrometry, fluorescence multiplex immunohistochemistry, and RNA pull-down mass spectrometry.
Results: Normally, testis-specific LINC01940 is aberrantly upregulated in GC and associated with poor prognosis. Functional assays demonstrated that LINC01940 promotes GC cell proliferation and invasion and confers resistance to cisplatin. Mechanistically, LINC01940 is stabilized by methyltransferase 16 (METTL16)/ insulin-like growth factor 2 messenger RNA binding protein 3 (IGF2BP3)-mediated N6-methyladenosine (m6A) modification, which enhances its ability to act as a scaffold promoting the interaction between the small ubiquitin-like modifier 2 (SUMO2) E3 ligase TATA-box binding protein associated factor 15 (TAF15) and Nucleolar protein 11 (NOL11), promoting the SUMOylation of NOL11 and enhancing its protein stability. This, in turn, increases ribosomal DNA transcription and ribosome biogenesis, thereby promoting GC progression and chemoresistance.
Conclusions: LINC01940 is a cancer-testis lncRNA that promotes GC progression and cisplatin resistance by enhancing ribosome biogenesis via the METTL16/IGF2BP3–TAF15–NOL11 axis. These findings suggest its potential as a prognostic biomarker and therapeutic target in GC.
Keywords LINC01940, SUMOylation, Gastric cancer, Ribosome biogenesis, Cancer drug resistance
Address and Contact Information 1 Department of Gastrointestinal Surgery, Affiliated Hospital of Nantong University, Medical School of Nantong University, 20 Xisi Street, Nantong 226001, Jiangsu, China
2 Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, 20 Xisi Street, Nantong 226001, Jiangsu, China
3 Nantong Key Laboratory of Gastrointestinal Oncology, Nantong 226001, China
4 Department of Pathology, Affiliated Hospital of Nantong University, Nantong 226001, China
5 Department of Graduate School, Dalian Medical University, Dalian 116000, China
6 Department of General Surgery, Qidong People’s Hospital/Qidong Liver Cancer Institute/Affiliated Qidong Hospital of Nantong University, Nantong 226200, China
*Corresponding author: Junjie Chen ntfyCJJ@ntu.edu.cn Yilin Hu hyl510@ntu.edu.cn Wanjiang Xue xuewanjiang@ntu.edu.cn
† Weijie Zang, Debiao Fan, and Zhuang Lu contributed equally to this work.
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No.  09DOI: 10.1186/s11658-025-00838-z Volume 31 (2026) - 30:09
Title PCSK9 INHIBITION AMELIORATES MICROPLASTIC-INDUCED ENDOTHELIAL REDOX IMBALANCE VIA SIRT6 MODULATION
Authors Nunzia D’Onofrio1,5†, Isabella Donisi1†, Vitale Del Vecchio2, Francesco Prattichizzo3, Valeria Pellegrini3, Michelangela Barbieri4,5, Antonio Ceriello3, Raffaele Marfella4,5, Giuseppe Paolisso4,5† and Maria Luisa Balestrieri1,5*†
Abstract Background: Microplastics (MPs) have emerged as significant environmental pollutants, posing a threat to ecosystems and humans. The presence of MPs in atherosclerotic plaques, exacerbating cardiovascular risk, has been recently reported. However, the molecular mechanism underlying the effects of MPs on the vascular endothelium are still undefined. In this regard, this study aims to investigate the effects of MPs on endothelial cell function and redox state and the underlying mechanisms.
Methods: Immortalized human aortic endothelial cells (teloHAEC), human umbilical vein endothelial cells (HUVEC), and human coronary artery endothelial cells (HCAEC) were treated with MPs in the form of polyethylene (PE) and polyvinyl chloride (PVC) alone (70 µg/mL) or combined PE (30 µg/mL) + PVC (30 µg/mL) (PE + PVC) for up to 48 h. The effects of MPs on cell viability were evaluated using CCK-8, and its role in endothelial function was evaluated by flow cytometric analyses, enzyme-linked immunosorbent assays (ELISA), and XF HS Seahorse bioanalyzer. Proprotein convertase subtilisin-kexin type 9 (PCSK9) levels were detected by reverse-transcription quantitative polymerase chain reaction (RT-qPCR) and immunoblotting. Molecular involvement of sirtuin 6 (SIRT6) was investigated through gene silencing.
Results: Our study demonstrated that PE and PVC, alone or in combination, upregulated inflammatory mediators monocyte chemoattractant protein-1 (MCP-1), vascular cell adhesion molecule-1 (VCAM1), and intercellular adhesion molecule-1 (ICAM1) (p < 0.001), modulated the expression of autophagy markers anti-autophagy related 5 (ATG5) and p62, impaired mitochondrial metabolism by reducing maximal and basal respiration and adenosine triphosphate (ATP) production (p < 0.001), promoted reactive oxygen species (ROS) accumulation (p < 0.001) and cell cycle perturbations (p < 0.01), and increased apoptosis cell death (p < 0.001). These events were accompanied by a downregulation of sirtuin 6 (SIRT6) expression (p < 0.01) and an upregulation of PCSK9, at protein and messenger RNA (mRNA) levels (p < 0.01). Treatment with the PCSK9 inhibitor (iPCSK9) evolocumab ameliorated MP-induced cellular redox state imbalance, mitochondrial metabolism alteration, and SIRT6 downregulated levels (p < 0.01). SIRT6 transient silencing experiments denied the beneficial effects of iPCSK9 treatment, indicating that the pleiotropic functions of iPCSK9 may occur, at least in part, via modulation of SIRT6 and Forkhead box O3 (FOXO3A) expression levels.
Conclusions: Overall, the results indicate that PCSK9 inhibition via evolocumab exhibits substantial promise in the prevention of MP-induced endothelial dysfunction, suggesting the PCSK9–SIRT6 axis as a new promising pathway to target in preventive strategies for cardiovascular risk caused by plastic pollution.
Keywords Microplastics, PCSK9 inhibition, Endothelial dysfunction, SIRT6, Inflammation
Address and Contact Information 1 Department of Precision Medicine, University of Campania Luigi Vanvitelli, Via L. De Crecchio 7, 80138 Naples, Italy
2 Department of Experimental Medicine, University of Campania Luigi Vanvitelli, Via Luciano Armanni 5, 80138 Naples, Italy
3 IRCCS MultiMedica, Via Fantoli 16/15, 20138 Milan, Italy
4 Department of Advanced Clinical and Surgical Sciences, University of Campania Luigi Vanvitelli, Piazza Miraglia, 80138 Naples, Italy
5 Research Center for Environmental Pollution and Cardiovascular Diseases, University of Campania Luigi Vanvitelli, Piazza Miraglia, 80138 Naples, Italy
*Corresponding author: Maria Luisa Balestrieri marialuisa.balestrieri@unicampania.it
† Nunzia D’Onofrio and Isabella Donisi share first authorship.
† Giuseppe Paolisso and Maria Luisa Balestrieri contributed equally to this work and share last authorship.
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No.  10DOI: 10.1186/s11658-025-00836-1 Volume 31 (2026) - 30:10
Title BEYOND THE MUTATIONS: SPATIOTEMPORAL REGULATION OF CFTR BY cAMP AND CALCIUM SIGNALING IN EPITHELIAL PHYSIOLOGY AND CYSTIC FIBROSIS
Authors Arpad Varga1,2,3, Aletta Kiss1,2,3, Tim Crul1,2,3, Tamara Madácsy1,2,3, Petra Pallagi1,2,3 and József Maléth1,2,3*
Abstract Cystic fibrosis (CF) is a life-shortening monogenic disease caused by mutations in the CFTR gene, but the functional expression of the cystic fibrosis transmembrane conductance regulator (CFTR) Cl−/HCO3− channel is determined by more than its genetic sequence. Beyond the well-known folding defect of the common F508del mutation, CFTR activity is dynamically modulated by a network of intracellular signaling pathways that control the channel’s gating, trafficking to, and retention at the apical membrane. Foremost is the cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) pathway, which drives CFTR opening via phosphorylation of its regulatory (R) domain and coordination by scaffolding proteins (e.g., A-kinase anchoring proteins (AKAPs) and Na+/H+ exchanger regulatory factor 1 (NHERF1)). Equally important, Ca2+-dependent signaling cascades provide complementary fine-tuning: Ca2+-bound calmodulin can directly bind and increase the CFTR open probability, Ca2+-activated kinases such as Ca2+/calmodulin-dependent protein kinase II (CaMKII) and the tyrosine kinase Pyk2 (with Src) can phosphorylate CFTR through noncanonical routes, and signaling intermediates such as IP3 receptor binding protein released with IP3(IRBIT) connect Ca2+ release to CFTR activation. These cAMP- and Ca2+-driven pathways intersect in specialized subcellular nanodomains, enabling precise spatiotemporal regulation of CFTR function. Clinically, although new CFTR modulator drugs have greatly improved outcomes, their effectiveness is limited by mutation-specific responses and incomplete restoration of channel activity. Understanding how cAMP–Ca2+ crosstalk governs CFTR in context can reveal novel therapeutic strategies targeting the channel’s regulatory microenvironment. This review highlights how compartmentalized cAMP and Ca2+ signals orchestrate CFTR function and discusses emerging approaches to harness this insight for better therapies across CF-affected organs.
Keywords Cystic fibrosis, CFTR regulation, cAMP signaling, Calcium signaling
Address and Contact Information 1 First Department of Medicine, University of Szeged, Szeged 6720, Hungary
2 HAS-USZ Momentum Epithelial Cell Signaling and Secretion Research Group, University of Szeged, Szeged 6720, Hungary
3 HCEMM-USZ Molecular Gastroenterology Research Group, University of Szeged, Szeged 6720, Hungary
*Corresponding author: József Maléth jozsefmaleth1@gmail.com; maleth.jozsef@med.u-szeged.hu
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No.  12DOI: 10.1186/s11658-025-00833-4 Volume 31 (2026) - 30:12
Title GPR43 DEFICIENCY AGGRAVATES SEPSIS BY PROMOTING GUT MICROBIOTA–DEPENDENT BARRIER DISRUPTION AND HIF-1α–ENO1 AXIS–MEDIATED M1 POLARIZATION OF MACROPHAGES
Authors Mingyang Tang1,2†, Hongru Li3†, Fei Tang4†, Yuanlong Shu1,2†, Bao Meng1,2, Qingyue Zhang1,2, Chengcheng Li1,2, Yuexin Xu1,2, Ying Xu1,2, Jingjing Pan1,2, Yanyan Liu1,2, Lifen Hu1,2, Cui Wang5*, Ting Wu1,2* and Jiabin Li1,2*
Abstract Background: GPR43, a receptor for short-chain fatty acids (SCFAs), is broadly expressed in intestinal epithelial and immune cells and is essential for preserving barrier integrity and immune homeostasis. Nevertheless, how GPR43 influences gut microbiota composition and intestinal barrier integrity while also regulating macrophage immunometabolism in the context of sepsis remains poorly understood.
Methods: A cecal ligation and puncture model was used to induce sepsis in mice. Survival, histopathology, and immune responses were compared between Gpr43−/− and wild-type mice; 16S ribosomal RNA (rRNA) sequencing and untargeted metabolomics were performed to evaluate gut microbiota composition and metabolic profiles. Antibiotic-mediated microbiota depletion and fecal microbiota transplantation were used to assess functional impacts. Bone marrow-derived macrophages were employed to investigate the effects of GPR43 deficiency on macrophage polarization. RNA sequencing, metabolic flux analysis, and Western blotting were conducted to explore the molecular mechanisms involved. Peripheral blood mononuclear cell samples from patients with sepsis were analyzed for clinical correlation.
Results: Gpr43−/− mice exhibited significantly reduced survival following CLP, along with impaired intestinal barrier function and elevated proinflammatory cytokine levels. Microbiota diversity and SCFA-producing bacteria were markedly decreased, accompanied by reduced SCFA levels in fecal metabolites. Fecal microbiota transplantation (FMT) partially restored gut function and survival in Gpr43−/− mice. GPR43-deficient macrophages displayed a strong M1-polarized phenotype with the upregulation of the glycolytic enzyme ENO1 and its upstream regulator HIF-1α. The inhibition of either ENO1 or HIF-1α reversed the proinflammatory phenotype. A clinical data analysis revealed that GPR43 expression was negatively correlated with IL-6, ENO1, and lactate levels.
Conclusions: GPR43 exerts a dual protective role in sepsis by maintaining gut microbiota homeostasis and barrier integrity and by modulating macrophage metabolism and polarization via the HIF-1α–ENO1 axis. This study provides novel insights into the GPR43 in pathogenesis of sepsis and suggests potential therapeutic targets for intervention.
Keywords GPR43, Macrophage, Sepsis, Glycolysis, ENO1
Address and Contact Information 1 Department of Infectious Diseases, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
2 Anhui Province Key Laboratory of Infectious Diseases, Anhui Medical University, Hefei 230022, China
3 Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
4 Department of Interventional Pulmonology and Endoscopic Diagnosis and Treatment Center, Anhui Chest Hospital, Hefei 230022, China
5 Department of Critical Care Medicine, The First Affiliated Hospital of Anhui Medical University, Hefei 230022, China
*Corresponding author: Cui Wang colorfulday23@126.com Ting Wu wutingf88945@163.com Jiabin Li lijiabin@ahmu.edu.cn
† Mingyang Tang, Hongru Li, Fei Tang, and Yuanlong Shu contributed equally to this work.
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No.  02DOI: 10.1186/s11658-025-00825-4 Volume 31 (2026) - 30:02
Title MPP7 INHIBITS TUMOR METASTASIS THROUGH PROMOTING SNAIL DEGRADATION IN CLEAR CELL RENAL CELL CARCINOMA
Authors Mi Zhang1, Juan Zhang1, Yan Zhou1, Andi Zhao2, Hui Wang3, Bo Wang4, Juan Li4, Peijun Liu4* and Jin Yang1,3,5,6*
Abstract Background: Tumor metastasis is a major factor of high recurrence and mortality in clear cell renal cell carcinoma (ccRCC), but its underlying mechanism remains elusive. This study focuses on investigating the impact and underlying molecular mechanisms of MAGUK p55 subfamily member 7 (MPP7) on the metastasis of ccRCC.
Methods: The clinical significance of MPP7 in patients with ccRCC was investigated based on The Cancer Genome Atlas (TCGA), Genotype Tissue Expression Project (GTEx) databases and clinical tissue samples. Slow aggregation, microscopic photography and immunofluorescence (IF) assay were applied to assess the effect of MPP7 on intercellular adhesion, cell morphology, and cytoskeletal F-actin, respectively. Transwell and wound-healing assays were used to detect cell migration and invasion. The quantitative real-time polymerase chain reaction (qRT-PCR), western blot, IF, co-immunoprecipitation (Co-IP), and immunoprecipitation-mass spectrometry (IP-MS) were applied to elucidate the underlying molecular mechanism.
Conclusions: Our work elucidated the role and molecular mechanism of MPP7 in migration and invasion regulation of ccRCC.
Keywords Clear cell renal cell carcinoma, Ubiquitin–proteasome system, Epithelial–mesenchymal transition, MPP7, Snail
Address and Contact Information 1 Phase I Clinical Trial Ward, The First Affiliated Hospital of Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an 710061, Shaanxi, China
2 Department of General Practice, The First Affiliated Hospital of Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an 710061, Shaanxi, China
3 Department of Medical Oncology, The First Affiliated Hospital of Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an 710061, Shaanxi, China
4 Translational Medicine Center, The First Affiliated Hospital of Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an 710061, Shaanxi, China
5 Cancer Center, The First Affiliated Hospital of Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an 710061, Shaanxi, China
6 Precision Medicine Center, The First Affiliated Hospital of Xi’an Jiaotong University, No 277 Yanta West Road, Xi’an 710061, Shaanxi, China
*Corresponding author: Peijun Liu liupeijun@xjtu.edu.cn Jin Yang yangjin@xjtu.edu.cn
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No.  15DOI: 10.1186/s11658-025-00839-y Volume 31 (2026) - 30:15
Title G-QUADRUPLEX STRUCTURES ARE KEY REGULATORS OF MAMMALIAN SPERMATOGENESIS
Authors Shuo Li1, Yixiao Ma1, Haoxin Shi1, Ruoyu Wang1, Chen Li1, Tian Zhang1, Chunyu Zhu3, Yanan Gu4, Ziyao Song1, Haoran Guo1, Mohan Dong2, Yu Li3, Zhen Li5, Ming-Qi Wang6, Weihong Wen7*, Fa Yang1* and Weijun Qin1*
Abstract Background: Male infertility, impacting 8–12% of couples globally, often lacks clear etiology. G-quadruplexes (G4s), noncanonical DNA structures, are implicated in genomic regulation but remain underexplored in spermatogenesis. This study investigates G4 dynamics and their roles in male fertility.
Methods: We employed antibody-based staining, cleavage under targets and tagmentation (CUT&Tag) sequencing, and a novel nanobody-based proximity labeling system (nanoG4BPL) to map G4 distribution and interacting proteins in mouse testicular cells. In vivo G4 stabilization with pyridostatin and clinical analysis of testicular tissues from patients with nonobstructive azoospermia (NOA) were conducted.
Results: G4 structures are enriched in testicular tissues, displaying stage-specific dynamics during spermatogonial differentiation, meiosis, and spermiogenesis. Genome-wide profiling revealed the dual roles of G4s in coordinating gene expression with active epigenetic marks and facilitating genome architecture via CTCF interactions. G4 stabilization disrupted double-strand break repair during meiosis, with nanoG4BPL identifying Nijmegen breakage syndrome 1 (NBS1) as a G4-interacting protein promoting phase separation for homologous recombination. Clinically, patients with NOA exhibited significantly elevated G4 levels in spermatocytes.
Conclusion: G4 structures are critical regulators of spermatogenesis, orchestrating gene expression, chromatin remodeling, and meiotic fidelity. Their dysregulation, particularly in patients with NOA, suggests a mechanistic link to male infertility, providing novel insights into its pathogenesis and highlighting potential avenues for future diagnostic or therapeutic exploration.
Keywords G-quadruplex, Spermatogenesis, DSB, HR, Male Infertility
Address and Contact Information 1 Department of Urology, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China
2 Department of Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an 710032, Shaanxi, China
3 Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, Shaanxi, China
4 Assisted Reproduction Center, Northwest Women and Children’s Hospital, Xi’an 710061, Shaanxi, China
5 Department of Human Anatomy, Histology and Embryology, Air Force Medical University, Xi’an 710032, Shaanxi, China
6 School of Pharmacy, Jiangsu University, Zhenjiang 212013, Jiangsu, China
7 Xi’an Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Medical Research, Northwestern Polytechnical University, Xi’an 710072, Shaanxi, China
*Corresponding author: Weihong Wen weihongwen@nwpu.edu.cn Fa Yang yangfa@fmmu.edu.cn Weijun Qin qinwj@fmmu.edu.cn
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No.  16DOI: 10.1186/s11658-025-00848-x Volume 31 (2026) - 30:16
Title MANY FACES OF MAMMALIAN NSD METHYLTRANSFERASES
Authors Eugenia A. Tiukacheva1,2, Yegor Vassetzky2,3*, Sergey V. Razin1,4, Dong Fang5 and Sergey V. Ulianov1,4*
Abstract Nuclear receptor-binding SET domain (NSD) proteins have been initially described as methyltransferases specific to lysine-36 in histone H3 and associated with active chromatin. However, their role in the regulation of transcription and in overall cellular physiology is much more complex, especially in mammals. The emerging diversity of their targets and, accordingly, the processes in which NSD proteins are involved, shows the importance of their noncanonical functions. A wide functionality apparently requires a complicated control system ensuring proper spatial and temporal activation of NSD methyltransferases. In this review, we discuss the role of NSD proteins in transcription, genome topology, mitosis, oncogenesis, immunity, DSB repair, and known mechanisms regulating their activity.

    Highlights
  • NSD proteins initially described as H3K36-specific methyltransferases methylate a wide range of nonhistone targets.
  • NSD proteins promote gene transcription by affecting RNA polymerase through elongation and transcription factors.
  • NSD1 promotes the spread of DNA methylation, preventing CTCF binding and, as a result, weakening TAD boundaries, while NSD2 strengthens existing TAD boundaries.
  • NSD1–3 affect oncogenesis, inflammation, immune response, and double-stranded breaks response through methylation of nonhistone proteins.
  • NSD proteins participate in the histone code and may also be involved in a universal post-translational modification (PTM) protein code.
Keywords NSD1, NSD2, NSD3, Histone methylation, H3K36me2, Chromatin structure
Address and Contact Information 1 Institute of Gene Biology, Moscow 119334, Russia
2 Koltzov Institute of Developmental Biology, Moscow 119334, Russia
3 CNRS UMR9018, Institut Gustave Roussy, 94805 Villejuif, France
4 Department of Molecular Biology, Faculty of Biology, Lomonosov Moscow State University, Moscow 119991, Russia
5 Life Sciences Institute, Zhejiang University, Hangzhou 310058, Zhejiang, China
*Corresponding author: Yegor Vassetzky yegor.vassetzky@gustaveroussy.fr Sergey V. Ulianov sergey.v.ulyanov@gmail.com
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No.  17DOI: 10.1186/s11658-025-00842-3 Volume 31 (2026) - 30:17
Title TARGETING INTEGRIN αVβ3–Ptgs2–mTOR SIGNALING RESCUES BONE FORMATION IN OSTEOPOROSIS: FROM MOLECULAR MECHANISM TOWARD THERAPY
Authors Changshun Chen1,2,3†, Jinyi Gu4†, Chenhui Yang1,2†, Fei Yang1,2, Zirui Liu1,2, Lei Wen1,2,3, Rongjing Chen1,2, Bin Geng1,2* and Yayi Xia1,2*
Abstract Background: Integrin αVβ3, a key ECM receptor, is essential for bone metabolism, yet its role in postmenopausal osteoporosis (PMOP) remains unclear. This study investigates the molecular mechanisms by which integrin αVβ3 regulates osteoblast function and bone homeostasis in PMOP.
Methods: Using clinical samples, OVX mice, and in vitro models, we analyzed integrin αVβ3 expression and its impact on osteogenesis. Clustered regularly interspaced short palindromic repeats (CRISPR)/Cas9-mediated knockout, multi-omics profiling, and protein interaction assays (Co-IP, BLI, and structural modeling) were employed to dissect the underlying pathway. An AAV9-based in vivo overexpression system was developed to evaluate therapeutic potential.
Results: Integrin αVβ3 was downregulated in PMOP patients and OVX mice, correlating with osteoblast dysfunction and reduced bone formation. Mechanistically, integrin αVβ3 deficiency upregulated Ptgs2, which directly bound to mammalian target of rapamycin (mTOR) via a hydrogen bond between Ptgs2-Glu52 and mTOR-Ser2159, inhibiting mTOR phosphorylation. This suppression disrupted mTORC1-S6K/4EBP1 signaling, impairing osteoblast proliferation and survival. Notably, AAV9-mediated integrin αVβ3 overexpression rescued bone loss in OVX mice.
Conclusions: Our findings unveil a novel integrin αVβ3–Ptgs2–mTOR axis in PMOP pathogenesis: estrogen deficiency reduces integrin αVβ3, enabling Ptgs2-mediated mTOR inhibition and osteogenic decline. This study identifies integrin αVβ3 as a potential therapeutic target to restore bone formation in osteoporosis.
Keywords Integrin αVβ3, Ptgs2, MTOR signaling, Postmenopausal osteoporosis, Osteoblast dysfunction
Address and Contact Information 1 Department of Orthopedics, Lanzhou University Second Hospital, Lanzhou 730030, China
2 Orthopedic Clinical Medical Research Center and Intelligent Orthopedic Industry Technology Center of Gansu Province, Lanzhou 730030, China
3 Department of Orthopedics and Trauma Surgery, Affiliated Hospital of Yunnan University, Kunming 650032, China
4 Institute of Pathogen Biology, School of Basic Medical Sciences, Lanzhou University, Lanzhou 730030, China
*Corresponding author: Bin Geng gengbing2024@163.com Yayi Xia xiayay@163.com
† Changshun Chen, Jinyi Gu, Chenhui Yang contributed equally to this work and shared the first authorship.
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No.  18DOI: 10.1186/s11658-025-00834-3 Volume 31 (2026) - 30:18
Title THE NEURO-IMMUNE INSIGHTS OF ITCH: PERIPHERAL MECHANISMS AND CENTRAL GLIAL CONTRIBUTIONS
Authors Zhe Li1,2†, Ning Yu3,4†, Sidi Feng5†, Xinrui Wang6†, Yu-Xia Chu7* and Xiaowen Liu1*
Abstract Itch is a common symptom of inflammatory, systemic, and neurological conditions and is often driven by persistent neuroinflammatory processes. This review explores the intricate mechanisms underlying itch, focusing on interactions among sensory neurons, immune mediators, and glial cells. Key peripheral pathways include activation of pruriceptors by histamine, interleukins, and chemokines, as well as inflammatory pathways dependent on Toll-like receptors (TLRs). These pathways promote the release of mediators such as interleukin-6 (IL-6) and C–C motif chemokine ligand 2 (CCL2). In the spinal cord, astrocytes and microglia contribute to itch amplification by releasing proinflammatory cytokines and activating signaling pathways such as signal transducer and activator of transcription 3 (STAT3) and TLR4. These processes drive central sensitization and facilitate the transition from acute to chronic itch in conditions such as atopic dermatitis, psoriasis, and allergic contact dermatitis. By summarizing advances in neuroimmune crosstalk and glial–neuronal interactions, this review identifies potential molecular targets for therapeutic strategies aimed at alleviating itch and improving patient outcomes.
Keywords Itch, Pruriceptors, Immune receptors, Glial cells
Address and Contact Information 1 Department of Anesthesiology, China-Japan Friendship Hospital, Beijing, China
2 Institute of Clinical Medical Sciences, China-Japan Friendship Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
3 State Key Laboratory of Common Mechanism Research for Major Diseases, Department of Human Anatomy, Histology and Embryology, Joint Laboratory of Anesthesia and Pain, Institute of Basic Medical Sciences Chinese Academy of Medical Sciences, School of Basic Medicine Peking, Neuroscience Center, Union Medical College, Beijing, China
4 Department of Neurology, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China
5 Dalian Medical University, Dalian, China
6 Department of Pharmacy, Beijing Chaoyang Hospital, Capital Medical University, Beijing, China
7 Department of Integrative Medicine and Neurobiology, School of Basic Medical Sciences, Institute of Acupuncture Research, Institutes of Integrative Medicine, Shanghai Key Laboratory of Acupuncture Mechanism and Acupoint Function, Shanghai Medical College, Fudan University, Shanghai 200032, China
*Corresponding author: Yu-Xia Chu yuxiachu@fudan.edu.cn Xiaowen Liu liuxiaowen@cjfh.org.cn
† Zhe Li, Ning Yu, Sidi Feng, and Xinrui Wang have contributed equally to this work.
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No.  19DOI: 10.1186/s11658-025-00844-1 Volume 31 (2026) - 30:19
Title THE MULTIPLE ROLES OF gt1-Cre IN THE GENERATION OF TRANSGENIC MICE
Authors Ze-Sen Feng1†, Jie Luo1†, Xiao-Cui Chen1†, Ping-Ping Zhao1, Shi-Tong Qiu1, Chun-Yu Wu1, Xiao-Rong Huang1, Bing-Chun Sun2, Xiao-Jun Guo1, Zhen-Nan Ye1*, Chen Yang1*, Hua-Feng Liu1* and Ji-Xin Tang1*
Abstract The Cre/loxP system continues to serve as a well-established and widely adopted strategy for generating conditional gene knockout or knock-in mouse models, facilitating precise genetic manipulations. The Ggt1 gene, which exhibits specific expression in proximal tubular epithelial cells (TECs) of the kidney, has been extensively employed as a Cre driver for tissue-specific gene targeting within these cells. In this study, to achieve conditional Fam134b knockout in proximal TECs, we generated Fam134b floxed mice and crossed them with Ggt1-Cre transgenic mice. After several generations of selective breeding, we successfully obtained conditional Fam134b knockout mice, which displayed specific deletion of the target gene in proximal TECs. This was confirmed by western blot analysis, which demonstrated a marked deficiency of the FAM134B protein in the renal cortex of these mice. During the mating experiments, we unexpectedly found that we could obtain systematic Fam134b knockout mice, suggesting that Ggt1-Cre might be expressed and functional in germ cells. Genomic and transcriptomic sequencing analysis unequivocally confirmed the deletion of exon 4, while western blot analysis revealed complete absence of FAM134B protein in both heart and kidney tissues of these knockout mice. Through the implementation of different mating strategies, we determined that Ggt1-Cre mediated gene knockout occurs in germ cells that have completed the first meiotic division, rather than in germ cells prior to this developmental stage. Furthermore, qPCR and western blot analyses demonstrated the expression of Cre driven by the Ggt1 promoter in both testes and ovaries, providing additional evidence for its germline activity. Lineage tracing experiments revealed that Ggt1-Cre is expressed in both the kidneys and testes of B6-G/R f/+; Ggt1-Cre transgenic mice, where it effectively catalyzes Cre recombinase activity, leading to the conversion of green fluorescent protein-expressing cells to red fluorescent protein-expressing cells. These findings collectively highlight that Ggt1-Cre is not only a reliable proximal TEC-specific Cre driver but also an effective germline-specific Cre driver. Consequently, it can be utilized to achieve gene knockout or overexpression in both proximal TECs and post-first meiotic division germ cells, thereby enabling in-depth in vivo functional studies of genes in these distinct cell types.
Keywords Cre/loxP system, CRISPR/Cas9, FAM134B, Gene knockout, Gene knock-in, Ggt1-Cre
Address and Contact Information 1 Department of Nephrology, National Clinical Key Specialty Construction Program (2023), Institute of Nephrology, Guangdong Provincial Key Laboratory of Autophagy and Major Chronic Non-Communicable Diseases, Key Laboratory of Prevention and Management of Chronic Kidney Disease of Zhanjiang City, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
2 Department of Gynecology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong, China
*Corresponding author: Zhen-Nan Ye yezhennan12@mails.ucas.ac.cn Chen Yang yangchen307@126.com Hua-Feng Liu liuhf@gdmu.edu.cn Ji-Xin Tang tangjixin@gdmu.edu.cn
† Ze-Sen Feng, Jie Luo and Xiao-Cui Chen have contributed equally to this work.
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No.  37DOI: 10.1186/s11658-025-00843-2 Volume 31 (2026) - 30:37
Title SLC25A11-MEDIATED REPROGRAMMING OF MITOCHONDRIAL REDOX STATE AND LIPID PEROXIDATION CONFERS NRF2-DEPENDENT FERROPTOSIS RESISTANCE IN BILIARY TRACT CANCER
Authors Yu-Yu Lin1†, Han-Hsi Kuo1†, Zhao-Jing He1, Hsin-Yi Chung2, Cheorl-Ho Kim3, Yi-Ru Pan4, Meng-Ju Wu5, Ming-Hsien Chan1, Chun-Nan Yeh4, Nai-Jung Chiang2,6,7, Ming-Huang Chen2,6* and Yu-Chan Chang1*
Abstract Background: Biliary tract cancer is a group of highly heterogeneous and metastatic malignancies of the biliary tract. Current clinical treatment strategies and diagnostic methods need further improvement to effectively manage this disease.
Methods: We performed multiomics integrative and in silico analyses of selected SLC25 family members. Cell models with SLC25A11 overexpression or knockdown can be used for various biological function assays and cell imaging. Animal models and clinical specimens can be used to evaluate prognosis and treatment.
Results: SLC25A11 inhibition significantly reduced cell migration and proliferation both in vitro and in vivo. In addition, loss of SLC25A11 leads to accumulation of TCA-related metabolites, alters mitochondrial homeostasis, and reduces mitochondrial membrane potential. In addition, we confirmed that lipid peroxidation and lipid ROS aggregation in mitochondria by SLC25A11-knockdown model. Based on our RNA sequencing data, inhibition of SLC25A11 reduces NRF2 expression and translocation, resulting in loss of interaction affinity with the ferroptosis suppressor FSP1 and subsequent reactivation of the ferroptosis machinery. We also showed that low levels of SLC25A11 and knockdown models can activate lipid peroxidation and related molecules ACSL4, LPCAT3, and PEBP1, further inducing ferroptosis. Furthermore, recruitment of ferrostatin-1 (Fer-1) antagonizes the ferroptosis state by reducing lipid peroxidation and blocking the expression levels of these related molecules.
Conclusions: Bringing all the evidence together, we added several important insights between ferroptosis and biliary tract cancer. We raised that SLC25A11 will serve as a novel prognostic factor and treatment strategy for biliary tract cancer.
Keywords Biliary tract cancer, SLC25A11, Mitochondrial homeostasis, NRF2, Ferroptosis
Address and Contact Information 1 Department of Biomedical Imaging and Radiological Sciences, National Yang Ming Chiao Tung University, Taipei, Taiwan
2 Center of Immuno-Oncology, Department of Oncology, Taipei Veterans General Hospital, 201 Shipai Road, Section 2, Taipei 112, Taiwan
3 Molecular and Cellular Glycobiology Unit, Department of Biological Sciences, SungKyunKwan University, Suwon, Gyunggi-Do 16419, Republic of Korea
4 Department of Surgery, Chang Gung Memorial Hospital, Chang Gung University, Taoyuan, Taiwan
5 Division of Gastroenterology, Department of Medicine, University of Massachusetts Chan Medical School, Worcester, MA, USA
6 School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan
7 National Institute of Cancer Research, National Health Research Institutes, Tainan, Taiwan
*Corresponding author: Ming-Huang Chen mhchen9@vghtpe.gov.tw Yu-Chan Chang yuchanchang@nycu.edu.tw
† Yu-Yu Lin and Han-Hsi Kuo contributed equally to this work.
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No.  13DOI: 10.1186/s11658-025-00809-4 Volume 31 (2026) - 30:13
Title MITOCHONDRIA–ENDOPLASMIC RETICULUM CONTACT SITES IN HEPATOCYTIC SENESCENCE
Authors Pavitra Kumar1, Mohsin Hassan1, Frank Tacke1 and Cornelius Engelmann1,2*
Abstract Inter-organelle communication via membrane contact sites (MCSs) is essential for the efficient functioning of eukaryotic cells, facilitating coordination among approximately 20 distinct organelles, each with unique metabolic profiles. Among these interactions, mitochondria–endoplasmic reticulum (ER) contacts (MERCs) are particularly significant, encompassing about 5% of the mitochondrial surface. Key proteins involved in MERCs include inositol 1,4,5-trisphosphate receptor (IP3R), voltage-dependent anion channel (VDAC), glucose-regulated protein 75 (GRP75), Sigma1 receptor (Sig-1R), vesicle-associated membrane protein (VAMP)-associated protein B (VAPB), protein deglycase DJ-1, and protein tyrosine phosphatase interacting protein 51 (PTPIP51), with new proteins continually being identified for their roles in these structures. At these contact sites, metabolic exchanges involve calcium (Ca2+), lipids, reactive oxygen species (ROS), and proteins. MERCs enable efficient molecular exchanges through temporary bridges mainly formed by the ER, the organelle with the largest surface area. These contacts are crucial for maintaining mitochondrial dynamics, which is essential for cellular homeostasis, and they are notably impacted in pathological states such as metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-related liver diseases (ALD), and viral hepatitis. Dysfunctional MERCs can lead to mitochondrial fragmentation, increased ROS production, impaired autophagy, and disrupted protein trafficking, thereby exacerbating senescence and cellular aging. Senescence is a cell fate initiated by stress, characterized by stable cell-cycle arrest and a hypersecretory state, and is an underlying cause of aging and many chronic conditions, including liver diseases. The hallmarks of senescence—such as macromolecular damage, cell cycle withdrawal, deregulated metabolism, and a secretory phenotype—are well established. However, recent studies have demonstrated that senescence is a heterogeneous process, with molecular markers varying according to the stressors that induce it. This review focuses on the functional aspects of MERCs in hepatic senescence and their impact on liver diseases, and explores the potential of targeting MERCs to address hepatocytic senescence.
Keywords Mitochondria, ER, Contact sites, MERCs, Calcium, Hepatocyte, Senescence
Address and Contact Information 1 Department of Hepatology and Gastroenterology, Medizinische Klinik M. S. Hepatologie und Gastroenterologie, Charité Universitätsmedizin Berlin - Campus Virchow-Klinikum, Augustenburger Platz 1, 13353 Berlin, Germany
2 Berlin Institute of Health (BIH), 10178 Berlin, Germany
*Corresponding author: cornelius.engelmann@charite.de
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No.  05DOI: 10.1186/s11658-025-00818-3 Volume 31 (2026) - 30:05
Title METHYLATION-INDUCED SILENCING OF AZGP1 ENHANCES PROSTATE CANCER METASTASIS BY STIMULATING TUMORAL GLYCOLYSIS
Authors Lu Li1†, Jinguang Luo2†, Linyue Zhao1†, Lu Tian3†, Jianfeng Wang4*, Yifei Cheng5* and Xiao Li6,7*
Abstract Background: Metastasis is the primary cause of mortality in patients with prostate cancer (PCa), yet effective treatments remain scarce. Identifying reliable biomarkers and understanding their underlying mechanisms is crucial for advancing clinical management.
Methods: Firstly, we integrated single-cell and bulk transcriptomic data and employed the Scissor tool to characterize tumor cells with metastatic advantages (termed metastatic cells). Then, independent predictive genes for metastasis were identified through univariate and multivariate regression analyses. The role of hub genes in PCa metastasis was further validated using multiple large datasets, malignant phenotype experiments, in vivo metastatic models, and a clinical-sample-based immunohistochemical cohort. Further, we explored the metabolic characteristics related to hub genes through unbiased functional annotation, and validated the upregulated glycolysis by measuring l-lactic acid production, extracellular acidification rates (ECAR), and oxygen consumption rates (OCR). Finally, multi-omics data were employed to investigate the promoter-methylation-dependent regulation of alpha-2-glycoprotein 1 (AZGP1) transcription, with methylation confirmed through PCa cell-based methylation-specific PCR (MSP) assays.
Results: AZGP1 was identified as an independent protective predictor of metastasis, which was validated in vitro and in vivo. Metabolic functional annotation revealed that glycolysis was upregulated in AZGP1-positive luminal cells. Consistently, overexpression of AZGP1 in PCa cells was associated with lower l-lactic acid levels, reduced ECAR, and increased OCR. In addition, DNA methylation at the cg26429636 region was linked to decreased transcriptional expression of AZGP1. MSP assays revealed an unmethylated pattern in PCa cells with high AZGP1 expression, and higher methylation levels in AZGP1-low cells.
Conclusions: Promoter methylation of AZGP1 leads to reduced transcriptional expression, thereby promoting glycolysis in tumor cells and facilitating metastasis. The detection of AZGP1 methylation levels offers a valuable reference for dynamic surveillance of PCa metastasis.
Keywords Prostate cancer, Metastasis, AZGP1, Glycolysis
Address and Contact Information 1 Department of Pathology, Nanjing Drum Tower Hospital, Affliated Hospital of Medical School, Nanjing University, Nanjing 210008, China
2 Department of Urology, First Affiliated Hospital of Bengbu Medical University, Bengbu, Anhui, China
3 State Key Laboratory of Quality Research in Chinese Medicine, School of Pharmacy, Macau University of Science and Technology, Macau 999078, China
4 Department of Urology, China–Japan Friendship Hospital, Beijing 100029, China
5 Department of Urology, Southeast University Zhongda Hospital, Nanjing 210009, China
6 Department of Urologic Surgery, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and Affiliated Cancer Hospital of Nanjing Medical University, Nanjing 210009, China
7 Department of Scientific Research, Jiangsu Cancer Hospital and Jiangsu Institute of Cancer Research and Affiliated Cancer Hospital of Nanjing Medical University, Nanjing, Jiangsu, China
*Corresponding author: Jianfeng Wang zryhyy1@126.com Yifei Cheng yifei_cheng@163.com Xiao Li leex91@163.com
† Lu Li, Jinguang Luo, Linyue Zhao, Lu Tian contributed equally to this work.
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No.  21DOI: 10.1186/s11658-025-00853-0 Volume 31 (2026) - 30:21
Title TGFβ PATHWAY REPRESSES HEPATIC RIBOSOME BIOGENESIS AND PROTEIN SYNTHESIS BY REGULATING p70S6K–S6RP PROTEINS
Authors Athanasios Stavropoulos1*, Vassiliki Stamatopoulou2, Eleftherios Pavlos1,3, Maria Manioudaki1, Stratigoula Sakellariou4, Constantinos Stathopoulos2 and Maria Xilouri1
Abstract Background: Transforming growth factor-beta (TGFβ)-superfamily signaling has been implicated in the regulation of hepatocyte growth and regeneration after acute or chronic liver injury. However, the precise mechanisms underlying TGFβ signaling in the distinct hepatic cell types during the progression of liver fibrosis remain largely unknown. We aim to identify the downstream molecular mechanisms of TGFβ-signaling modulation on hepatocytes.
Methods: To modulate TGFβ-superfamily signaling in vivo, Smad3 or Smad7 were adenovirally overexpressed in mouse liver. Parallelly, hepatosphere cultures were treated with recombinant TGFβ1 and subjected to transcriptomic analysis. These data were compared with transcriptomes from Smad7-overexpressing livers. To broaden the analysis, publicly available RNA-seq datasets from TGFβ-treated hepatic stellate cells and hepatocellular carcinoma lines were meta-analyzed. Finally, human liver tissues from cirrhotic and healthy individuals were examined for fibrosis and ribosome biogenesis markers to validate murine findings.
Results: Acute hepatic overexpression of Smad3 induced a transient fibrotic phenotype in the mouse liver. In hepatosphere cultures, TGFβ1 treatment suppressed key components of ribosomal assembly, whereas Smad7 overexpression exerted the opposite effect in the mouse liver, thus highlighting ribosome biogenesis as a major cellular process negatively regulated by the TGFβ superfamily. Inhibition of TGFβ signaling via Smad7 increased hepatic protein content (a critical parameter for restoring hepatic homeostasis upon liver damage), activated the nucleolus, and prompted the production of ribosomal pre-mRNAs without affecting p53 levels. Mechanistically, SMAD7-mediated inactivation of TGFβ signaling triggered selectively the p70S6K–S6RP regulatory axis, independently of cellular myelocytomatosis oncogene (c-MYC), mechanistic target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK) pathways. Importantly, analysis of hepatic tissue from cirrhotic patients and controls unveiled a negative association between TGFβ signaling and ribosome biogenesis in fibrotic livers. Complementary meta-analysis of RNA-seq data demonstrated that TGFβ regulates ribosome biogenesis in a cell type-specific manner, suppressing it in hepatocytes while enhancing it in hepatic stellate cells, consistent with their distinct functional states and transcriptional landscapes.
Conclusions: Collectively, our data reveal a SMAD-dependent regulatory role of TGFβ-superfamily signaling on hepatocytes that is tightly connected with hepatic growth to ensure proper energy homeostasis and metabolism. This is a critical regeneration parameter, which is closely related to the restoration of hepatic mass, especially following liver injury and fibrosis.
Keywords Cell signaling, Cirrhosis, Liver growth, Regeneration, Ribosome, Smads, Translation
Address and Contact Information 1 Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece
2 Department of Biochemistry, School of Medicine, University of Patras, Patras, Greece
3 Division of Basic Sciences, School of Medicine, University of Crete, Heraklion, Greece
4 First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
*Corresponding author: Athanasios Stavropoulos astavrop@bioacademy.gr
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No.  08DOI: 10.1186/s11658-025-00837-0 Volume 31 (2026) - 30:08
Title HETEROGENEITY OF GLUCOSE METABOLISM AND UPTAKE IDENTIFIES DISTINCT CANCER CELL AND CANCER STEM CELL PHENOTYPES
Authors Zuzana Tylichova1*, Martin Krkoska1, Vaclav Hrabal1, Michaela Stenckova1, Borivoj Vojtesek1 and Philip J. Coates1*
Abstract Background: Tumor cells show phenotypic heterogeneity, including a small subpopulation of cancer stem-like cells (CSCs) that are responsible for maintaining tumor growth and metastasis. Altered glucose metabolism is a characteristic feature of cancer cells, which often display increased aerobic glycolysis alongside mitochondrial oxidative respiration (the Warburg effect). However, there is evidence that CSCs exhibit distinct glucose metabolism compared with the tumor cell bulk, with increased mitochondrial activity and oxidative respiration. Thus, identifying individual cells with different modes of glucose metabolism may serve as a common identifier of CSCs, and these metabolic differences would allow selective therapeutic targeting.
Methods: We investigated the levels of enzymes involved in glycolysis and oxidative respiration, together with glucose uptake and mitochondrial membrane potential in individual cancer cells. These parameters were correlated with each other and with CSC markers.
Results: We show considerable heterogeneity of metabolic markers in individual tumor cells. Surprisingly, high glucose uptake correlates with high mitochondrial membrane potential, indicating that increased oxidative respiration and aerobic glycolysis coexist rather than showing an inverse correlation. We also show that colonies derived from cells with high mitochondrial membrane potential exhibit heterogeneous metabolic parameters, demonstrating that metabolic profiles are not hard-wired. Public gene expression profiling data indicated similar inconsistent metabolic features of CSCs.
Conclusions: The data reveal inherent heterogeneity and plasticity of glucose metabolism and mitochondrial membrane potential in tumor cells, with evidence for a subpopulation that possesses both increased glucose uptake and increased mitochondrial membrane potential, with implications for therapeutic targeting of metabolism in cancer.
Keywords Glucose metabolism, Cancer stem cells, Mitochondria, ALDH, LDH, SDH, GLUT1
Address and Contact Information 1 RECAMO, Masaryk Memorial Cancer Institute, Zluty Kopec 7, Brno 656 53, Czech Republic
*Corresponding author: Zuzana Tylichova zuzana.tylichova@mou.cz Philip J. Coates philip.coates@mou.cz
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No.  27DOI: 10.1186/s11658-025-00845-0 Volume 31 (2026) - 30:27
Title HNF4A P2 ISOFORM ALLEVIATES KIDNEY FIBROSIS BY INHIBITING DEDIFFERENTIATION OF PROXIMAL TUBULAR CELLS THROUGH JAG1/NOTCH SIGNALING
Authors Guiya Jiang1†, Xun Lu3†, Rui Cao1†, Houliang Zhang1†, Yue Gao4, Kai Lu2, Lei Zhang2, Guangyuan Zhang2, Jianping Wu2, Bin Xu2, Jian Zhong5*, Jin Sun6*, Ming Chen2 and Shuqiu Chen2*
Abstract Background: Tubulointerstitial fibrosis is a critical and irreversible process of chronic kidney disease. Dedifferentiated proximal tubular cells (PTCs) after injury are important for tubulointerstitial fibrosis. Hepatocyte nuclear factor 4 alpha (HNF4A) is the main regulatory factor for PTC differentiation. However, its role in PTC dedifferentiation and kidney fibrosis remains unclear.
Methods: To investigate the role of HNF4A in kidney fibrosis, bioinformatics analysis and in vivo models were used to evaluate its expression in kidney tissues. The mechanisms through which the HNF4A P2 isoform inhibits kidney fibrosis were examined by using both in vivo and in vitro models.
Results: In this study, we revealed that the sustained downregulation of HNF4A expression was a key characteristic of abnormally repaired PTCs after injury and was associated with cell dedifferentiation. It was confirmed that the HNF4A P2 isoform, rather than the P1 isoform, inhibited TGF-β1-induced PTC dedifferentiation. The activation of fibroblasts, which was induced by dedifferentiated PTCs through paracrine signalling, was also inhibited. In vivo experiments confirmed that HNF4A P2 was more effective than HNF4A P1 was in alleviating kidney fibrosis. Mechanistically, on one hand, HNF4A P2 antagonized the TGF-β1-induced dedifferentiation of PTCs by inhibiting the JAG1/NOTCH pathway. On the other hand, the distinct structure of HNF4A P2 from that of P1 made it unaffected by TGF-β1-activated SRC, allowing HNF4A P2 to perform transcriptional regulatory functions.
Conclusions: These findings suggest that targeting the HNF4A P2 isoform could serve as a novel therapeutic strategy to alleviate kidney fibrosis.
Keywords HNF4A, Isoform, Kidney fibrosis, Tubular dedifferentiation
Address and Contact Information 1 Urology Department, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, Jiangsu, China
2 Urology Department, Zhongda Hospital, Southeast University, Nanjing, Jiangsu, China
3 Department of Urology, Children’s Hospital of Nanjing Medical University, Nanjing 210000, China
4 Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN, USA
5 Zhangjiagang TCM Hospital Affiliated to Nanjing University of Chinese Medicine/Zhangjiagang Traditional Chinese Medicine Hospital, Zhangjiagang 215000, Suzhou, China
6 Department of Urology, Xuyi County People’s Hospital, No.28 Hongwu Avenue, Xuyi County, Huaian 223001, China
*Corresponding author: Jian Zhong zhongjie_218@163.com Jin Sun 1261516421@qq.com Shuqiu Chen chenshuqiuzdyy@163.com
† Guiya Jiang, Xun Lu, Rui Cao and Houliang Zhang contributed equally to this work.
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No.  23DOI: 10.1186/s11658-025-00856-x Volume 31 (2026) - 30:23
Title TARGETING THE SIRTUIN 6–NF-κB p65 AXIS BY 6-HYDROXYHYOSCYAMINE HYDROBROMIDE: A DEACETYLATION-DRIVEN NEW THERAPY FOR DIABETIC WOUNDS
Authors Junren Chen1†, Siqi Qin1†, Ziwei Xing1, Feng Wan1, Jie Yin1, Cheng Peng1* and Dan Li1*
Abstract Background: Diabetic wounds are a debilitating complication of diabetes mellitus with a high rate of amputation and mortality. 6-Hydroxyhyoscyamine hydrobromide (6-HH) is a belladonna alkaloid with smooth-muscle-relaxing and microcirculation-enhancing properties, yet its role in diabetic wounds remains unknown.
Methods: In vivo, diabetic wounds were established in streptozotocin (STZ)-induced type 1 diabetic mice, high fat diet (HFD)/STZ-induced type 2 diabetic mice, and db/db diabetic mice to investigate the therapeutic effects of 6-HH, and skin samples were collected for hematoxylin and eosin (H&E) and Masson’s trichrome staining, immunofluorescence, RNA-seq analysis, and western blotting. In vitro, the mechanism of action of 6-HH on cytokines, nuclear factor kappa B (NF-κB) signals, and the interaction between sirtuin 6 (SIRT6) and p65 in lipopolysaccharide (LPS)-induced macrophages were detected by using enzyme-linked immunosorbent assay (ELISA), western blotting, reverse-transcription quantitative polymerase chain reaction (RT-qPCR), immunofluorescence, and immunoprecipitation, while molecular docking was used to evaluate the binding energy between 6-HH and SIRT6 protein. Coculture systems of THP-1 cells–human umbilical vein endothelial cells (HUVECs)/immortalized human keratinocytes (HaCaTs) were established to investigate the effects of 6-HH on cross-talk between macrophages and endothelial cells/keratinocytes. SIRT6-specific inhibitor Oss_128167 was applied in vitro and in vivo to verify the mechanism of 6-HH in diabetic wound healing.
Results: 6-HH exhibited excellent pro-healing effect in the three types of diabetic mouse model. RNA-seq analysis found that 6-HH recovered diabetic-induced aberrant expression changes of genes in the local wounds, especially those related to M1 macrophage polarization with downregulation of Toll-like receptor (TLR) signals and nicotinamide adenine dinucleotide phosphate (NADP+) nucleosidase activity. Molecular docking analysis found that 6-HH could effectively bind to the active site of the SIRT6 protein. Remarkably, decline of SIRT6 in M1 macrophages resulted in lysine hyperacetylation, while activation and stabilization of SIRT6 by 6-HH suppressed M1 macrophage polarization and hyperacetylation through inhibiting p65 transcription with deacetylation of p65Lys310 and H3K9, contributing to improve angiogenesis and re-epithelization through interaction between macrophages and endothelial cells/keratinocytes. However, pharmacological inhibition of SIRT6 reversed the action of 6-HH in macrophages and diabetic wounds.
Conclusions: Collectively, deacetylase SIRT6 might be a direct pharmacological target of 6-HH that downregulates the hyperacetylated state of macrophages, thus contributing to diabetic wound healing.
Keywords SIRT6, Deacetylation, Macrophage polarization, 6-Hydroxyhyoscyamine hydrobromide, Diabetic wound
Address and Contact Information 1 Key Laboratory of Standardization of Chinese Medicine (Ministry of Education), Chinese Medicine Germplasm Resources Innovation and Effective Uses Key Laboratory of Sichuan Province, School of Pharmacy, Chengdu University of Traditional Chinese Medicine, 1166 Liutai Road, Wenjiang District, Chengdu 611137, China
*Corresponding author: Cheng Peng pengcheng_cd@126.com Dan Li lidan@cdutcm.edu.cn
† Junren Chen and Siqi Qin have contributed equally to this manuscript.
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No.  32DOI: 10.1186/s11658-026-00860-9 Volume 31 (2026) - 30:32
Title COGNITIVE–EXERCISE DUAL-TASK TRAINING DELAYS NATURAL AGING/D-GALACTOSE-INDUCED COGNITIVE DECLINE IN MICE
Authors Zi-Man Zhu1,2, Teng-Teng Dai3, Rong Zhang3, Pei-Ling Huang4, Ji-Lin Wu1,2, Li Song1,2 and Wei-Jun Gong4*
Abstract Background: Cognitive–exercise dual-task training has been shown to enhance cognitive function through mechanisms such as suppression of chronic inflammation, reduction of oxidative stress, and enhancement of synaptic plasticity. However, the precise mechanisms underlying the ability of dual-task training to delay aging-related cognitive decline remain incompletely understood.
Methods: Aged male C57BL/6J mice were subjected to a 12-week intervention program consisting of cognitive training, exercise, or cognitive–exercise dual-task training. Cognitive and physical function were assessed using a battery of behavioral tests, including the open field test, elevated plus maze test, inverted grid test, wire hanging test, rotarod test, novel object recognition test, novel object localization test, eight-arm maze test, and Morris water maze test. Hippocampal aging and associated molecular changes were assessed using multiple techniques, including terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, Nissl staining, immunohistochemistry, immunofluorescence, flow cytometry, quantitative polymerase chain reaction, Western blotting, co-immunoprecipitation, and dual-luciferase reporter assays. In addition, we established in vitro models of cellular senescence using d-galactose, RNA overexpression/silencing models utilizing siRNA, and Ephrin type-B receptor 2 (EphB2) inducer/inhibitor models to explore specific molecular mechanisms.
Results: Age-related upregulation in microRNA (miR)-204 and downregulation in long noncoding RNA (lncRNA) nuclear enriched abundant transcript 1 (NEAT1) were observed to disrupt Ephrin-B1 (EFNB1)/EphB2 interactions, leading to reduced cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway activation. These alterations were implicated in the pathogenesis of aging-related cognitive decline. Timely interventions, especially cognitive–exercise dual-task, were found to attenuate these phenomena, thereby delaying the progression of aging-related cognitive decline.
Conclusions: Timely intervention during the aging process can effectively delay the progression of cognitive decline. The effects of cognitive–exercise dual-task training may surpass those of single-task interventions with either cognitive training or exercise alone.
Keywords Aging, Cognitive decline, Dual-task, microRNA
Address and Contact Information 1 Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China
2 School of Beijing Rehabilitation Medicine, Capital Medical University, Beijing, China
3 The Second Clinical Medical College of Yunnan University of Chinese Traditional Medicine, Yunnan, China
4 Department of Neurological Rehabilitation, Beijing Rehabilitation Hospital, Capital Medical University, Beijing 100144, China
*Corresponding author: Wei-Jun Gong gwj197104@ccmu.edu.cn
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No.  11DOI: 10.1186/s11658-025-00846-z Volume 31 (2026) - 30:11
Title INHIBITION OF THE RORC/GPX4 MEDIATED FERROPTOSIS REGULATORY AXIS SUPPRESSES TUMOR GROWTH AND ALLEVIATES ENZALUTAMIDE RESISTANCE IN PROSTATE CANCER
Authors Yan Li1,2†, Bingqi Zhang2†, Zhongmin Zhang1,2, Wei Yan1,2, Haoyu Wang1,2, Xun Xu1,2, Anqi Lv2, Zhengming Liao1,2* and Lang Guo1,2*
Abstract Background: Patients with castration-resistant prostate cancer (CRPC) often develop resistance following long-term enzalutamide treatment. Building upon previous research, we aims to further explore the effect of ilicicolin A (ili-A) on enzalutamide resistance and to elucidate the underlying resistance mechanisms.
Methods: Proliferation, migration, and invasion of prostate cancer (PCa) cells were evaluated by 5-ethynyl-2′-deoxyuridine (EdU) assays, colony formation, scratch, and Transwell. Cell Counting Kit 8 (CCK-8) was used to assess the efficacy of drug inhibition in CRPC cells. The expression of tumor cell apoptotic proteins and ferroptosis was assessed using western blot (WB) analysis. Coimmunoprecipitation (Co-IP) and proximity ligation assay (PLA) were used to identify the mechanism of interaction between ilicicolin A and ferroptosis. Tumor transplantation experiments with mice were conducted to confirm findings.
Results: Ili-A showed dose-dependent inhibition of PCa cells including C4-2B and 22Rv1 cell lines. The overexpression of the RORC gene activated the expression of ferroptosis-related proteins, such as FTH1, GPX4 and SLC7A11, and enhanced proliferation of PCa cells. WB experiments indicated that RORC upregulated AR and AR-V7. An enzalutamide-resistant C4-2B cell line revealed that RORC serves as a gene target for enzalutamide resistance. Finally, it was observed that ili-A could suppress CRPC cells proliferation by downregulating RORC expression, thereby promoting ferroptosis and enhancing the sensitivity to enzalutamide.
Conclusions: Ili-A inhibited RORC expression, increased malondialdehyde (MDA) content, suppressed glutathione (GSH) production, released free Fe2+, increased reactive oxygen species (ROS), activated the ferroptosis pathway, enhanced enzalutamide sensitivity, and inhibited CRPC cell proliferation. Furthermore, ili-A enhances the interaction between ROR-γ and GPX4.
    Highlights:
  • On the basis of previous studies, we further explored the relationship between the enhancement of enzalutamide drug sensitivity by ilicicolin A and the ferroptosis phenotype.
  • Lentivirus-transfected cells were used for subcutaneous tumor transplantation in nude mice.
  • Erastin, an iron death inducer, was used as a drug control in animal experiments to explore the mechanism of enzalutamide resistance.
  • Co-IP and PLA experiments were used to deeply explore the relationship between RORC, a potential drug resistance target of enzalutamide, and ferroptosis.
  • Tightly combine ilicicolin A with the enzalutamide resistance target RORC.
Keywords Castration-resistant prostate cancer, Ilicicolin A, Ferroptosis, Enzalutamide, Drug resistance, Orphan nuclear receptor
Address and Contact Information 1 Department of Urology, Hubei Provincial Hospital of Traditional Chinese Medicine, Affiliated Hospital of Hubei University of Chinese Medicine, Hubei Sizhen Laboratory, Hubei University of Chinese Medicine, Wuhan 430000, Hubei, China
2 Hubei University of Chinese Medicine, No.1, Tanhualin, Wuchang District, Wuhan 430000, Hubei, China
*Corresponding author: Zhengming Liao lzmwhu@163.com Lang Guo guol199110@163.com
† Yan Li and Bingqi Zhang contributed equally to this work and are co-first authors for this paper.
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No.  24DOI: 10.1186/s11658-025-00841-4 Volume 31 (2026) - 30:24
Title VPS34-IN1 POTENTIATES STING-DEPENDENT ACTIVATION IN HUMAN CAL-1 CELLS
Authors Paulo Antas1, Mariana D. Machado1, Fátima Leite-Pinheiro1,2, Daniela Barros1,2, Carlota Ramalhinho1,3, Andreia Mendes1,2, Beatriz H. Ferreira1,3, Daniela Carvoeiro1, Luís F. Mendes1,4, Marisa Reverendo1,2, Iola F. Duarte3,4, Miwako Narita5, Bing Su6, Rafael J. Argüello2, Beatrice Nal2, Philippe Pierre1,2,6*, Catarina R. Almeida1* and Evelina Gatti1,2*
Abstract Inhibition of the phosphatidylinositol kinase vacuolar protein sorting 34 (VPS34) with the pharmacological compound VPS34-IN1 has a range of effects on the dynamics of endosomes. While VPS34 inhibition has been previously suggested as a potential therapeutic approach for treating certain cancers, our findings indicate that it has minimal cytotoxic effects on the leukemic blastic plasmacytoid dendritic cell neoplasm (BPDCN) CAL-1. However, we also found that VPS34-IN1 interferes with the function of this plasmacytoid dendritic cell (pDC) line, by inhibiting Toll-like receptor (TLR)7 signaling. In contrast, VPS34-IN1 triggers activation of the stimulator of interferon genes (STING) and significantly enhances cellular response to the STING agonist 2′3′-cyclic guanosine monophosphate-adenosine monophosphate (2′3′-cGAMP) with increased expression of type I interferons (IFNs). Inhibition of protein synthesis by VPS34-IN1 appears to be central to this synergy with STING activation. Thus, despite their limited toxicity toward different cancer lines, VPS34-IN1 may represent a promising compound to promote expression of type I IFNs and thus antitumoral immunity.
Keywords BPDCN, Chemotherapy, CL307, Immunotherapy, STING, Type I interferon, PtdIns 3-kinase
Address and Contact Information 1 Institute of Biomedicine (iBiMED), Department of Medical Sciences, University of Aveiro, 3810-193 Aveiro, Portugal
2 Aix Marseille Université, CNRS, INSERM, CIML, 13288 Marseille Cedex 9, France
3 Department of Chemistry, CICECO, Aveiro Institute of Materials, University of Aveiro, 3810-193 Aveiro, Portugal
4 LAQV-REQUIMTE, Department of Chemistry, University of Aveiro, Aveiro, Portugal
5 Faculty of Medicine, School of Health Sciences, Niigata University, Niigata 951-8518, Japan
6 Department of Microbiology and Immunology, Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, People’s Republic of China
*Corresponding author: Philippe Pierre pierre@ciml.univ-mrs.fr Catarina R. Almeida cra@ua.pt Evelina Gatti gatti@ciml.univ-mrs.fr
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No.  26DOI: 10.1186/s11658-025-00855-y Volume 31 (2026) - 30:26
Title KERATINIZATION-RELATED GENE SIGNATURE PREDICTING SURVIVAL AND RESPONSE TO RADIATION IN PATIENTS WITH HPV-NEGATIVE HEAD AND NECK SQUAMOUS CELL CARCINOMA VIA REGULATION OF CORNIFICATION AND INTEGRIN SIGNALING
Authors Min Kyeong Lee1, Harim Joo1, Minji Bae1, Yeonseo Lee1, Joo-Kyung Noh1, Young Chan Lee2, Jung Woo Lee3, Soonki Min4, Moonkyoo Kong4, Seong-Gyu Ko5 and Young-Gyu Eun1,2*
Abstract Head and neck squamous cell carcinoma (HNSCC) is a highly heterogeneous malignancy associated with poor prognostic outcomes. Despite ongoing efforts to identify reliable biomarkers for prognosis, the clinical utility of these markers remains limited owing to the need for further validation and deeper mechanistic insights. In this study, we developed and validated a novel keratinization-related gene signature (KRGS) to predict prognosis and radiation therapy (RT) response in human papillomavirus (HPV)-negative HNSCC using data from The Cancer Genome Atlas (TCGA). The 16-gene KRGS effectively stratified patients with HNSCC into two subgroups with significantly differing survival outcomes. KRGSlow, characterized by low KRGS expression, exhibited poorer survival and reduced sensitivity to RT, while KRGShigh, with high KRGS expression, was associated with more favorable survival outcomes and enhanced RT responsiveness. Functional validation, both in vitro and in vivo, demonstrated that keratinization activation through all-trans retinoic acid (ATRA) treatment upregulated the cornified envelope and sensitized HNSCC cells to RT. The enhanced response to RT was further associated with the upregulation of eight KRGS-related genes and increased expression of involucrin (IVL), a key regulator of terminal differentiation during cornification. Notably, the combination of ATRA and IR reduced radioresistance in HNSCC cells, which was linked to the downregulation of integrin alpha-1 (ITGA1) expression. These findings provide new insights into the role of keratinization in modulating radioresistance and suggest that KRGS-driven activation of keratinization, in combination with RT, may represent a promising therapeutic strategy to overcome resistance in HNSCC.
Keywords HPV-negative HNSCC, KRGS, Radiation therapy, Keratinization
Address and Contact Information 1 Department of Biomedical Science and Technology, Graduate School, Kyung Hee University, Seoul, Republic of Korea
2 Department of Otolaryngology-Head and Neck Surgery, Kyung Hee University School of Medicine, Kyung Hee University Medical Center, #23 Kyungheedae-Ro, Dongdaemun-Gu, Seoul 02447, Republic of Korea
3 Department of Oral and Maxillofacial Surgery, School of Dentistry, Kyung Hee University, Seoul, Korea
4 Department of Radiation Oncology, Kyung Hee University School of Medicine Kyung Hee University Medical Center, Seoul, Republic of Korea
5 Department of Preventive Medicine, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
*Corresponding author: Young-Gyu Eun ygeun@khu.ac.kr
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No.  28DOI: 10.1186/s11658-026-00858-3 Volume 31 (2026) - 30:28
Title ROLE OF LONP1 IN HUMAN DISEASES: MOLECULAR MECHANISMS AND THERAPEUTIC POTENTIAL
Authors Mingkang Li1*, Anguo Wang2, Chengchun Tang3, Yong Qiao3, Wenkang Zhang3* and Yamei Wu2*
Abstract Mitochondria, the primary energy producers in eukaryotic cells, depend on an intricate protein quality control (PQC) system to preserve their functional integrity. Lon protease 1 (LONP1), an adenosine triphosphate (ATP)-dependent serine protease localized in the mitochondrial matrix, maintains mitochondrial proteostasis through selective degradation of misfolded and oxidatively modified proteins. Beyond its proteolytic activity, LONP1 not only acts as a molecular chaperone facilitating protein folding but also directly binds to mitochondrial DNA (mtDNA), suggesting a multifunctional role in mitochondrial genome regulation. LONP1 is tightly regulated through multilayered mechanisms spanning transcriptional control, epigenetic modulation, and post-translational modifications. Emerging evidence establishes mechanistic links between LONP1 and the pathogenesis of various human diseases. In this review, we comprehensively summarize the structural features and multifunctional roles of LONP1, with particular emphasis on its disease-associated molecular mechanisms. We further evaluate existing pharmacological modulators of LONP1 activity, providing a theoretical basis for the development of new therapeutic strategies for related diseases.
Keywords Lon protease 1, Mitochondrial homeostasis, Cell death and proliferation, Human diseases, Therapeutic targets
Address and Contact Information 1 Department of Cardiology, Hainan General Hospital, Hainan Affiliated Hospital of Hainan Medical University, No. 19 Xiuhua Road, Haikou 570311, Hainan, People’s Republic of China
2 Reproductive Medical Center, Hainan Women and Children’s Medical Center, No. 75 Longkun South Road, 570206 Haikou, Hainan, People’s Republic of China
3 Department of Cardiology, Zhongda Hospital, Southeast University, No. 87 Dingjiaqiao, Nanjing 210009, Jiangsu, People’s Republic of China
*Corresponding author: Mingkang Li limingkang0611@hotmail.com Wenkang Zhang zwk96@126.com Yamei Wu 15595799860@163.com
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No.  20DOI: 10.1186/s11658-026-00859-2 Volume 31 (2026) - 30:20
Title TSP50 ATTENUATES METABOLIC DYSFUNCTION-ASSOCIATED STEATOTIC LIVER DISEASE VIA SCD1 DEGRADATION-MEDIATED SUPPRESSION OF HEPATOCYTE LIPOGENESIS
Authors Jiujia Liang1,2,3, Zhihui Luan4, Rong Jin2, Rina Su1, Jiarong Ge4, Xiao Tian1, Chunxue Niu1, Jiawei Li1, Xiaoli Li2, Feng Gao3, Zhenbo Song1, Luguo Sun1, Guannan Wang3, Lihua Zheng3, Ying Sun2, Lei Liu3, Yongli Bao3, Shuyue Wang1 & Xiaoguang Yang2
Abstract Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a major contributor to chronic liver disease worldwide, yet the molecular mechanisms driving its pathogenesis remain incompletely defined. Although dysregulated hepatic lipogenesis is a well-established driver of MASLD progression, the role of testes-specific protease 50 (TSP50)—an enzyme with demonstrated oncogenic functions in multiple cancers—in hepatic lipid metabolism and its potential involvement in the development of MASLD remains unexplored.
Methods: The study utilized the STelic Animal Model (STAM) along with high-fat/high-cholesterol plus fructose (HFF) and methionine-choline deficient (HFMCD) dietary models to evaluate the functional role of TSP50 in MASLD progression. Hepatocyte-specific knockout and AAV-mediated TSP50 reconstitution were performed to assess cell-autonomous effects. Mechanistic insights were gained through biochemical analyses of lipid metabolism pathways and protein interaction studies.
Results: TSP50 deficiency markedly accelerated MASLD progression across all experimental models, promoting hepatic steatosis, inflammation and fibrosis while increasing susceptibility to hepatocellular carcinoma (HCC). Conversely, TSP50 supplementation exerted protective effects against MASLD development. Furthermore, we identified a novel regulatory mechanism whereby TSP50 directly interacts with and degrades stearoyl-CoA desaturase 1 (SCD1) through its catalytic hydrolase activity, thereby suppressing de novo lipogenesis. The inhibitor of SCD1 rescued hepatic TSP50 knockout induced lipid accumulation and liver injury during MASLD.
Conclusions: Our study reveals the role of TSP50 in hepatic lipid metabolism, identifying it as a novel regulator of hepatic de novo lipogenesis that exerts protective effects against MASLD through catalytic degradation of SCD1. These findings not only advance our understanding of MASLD pathogenesis but also offer novel insights for developing therapeutic strategies.
Keywords TSP50, SCD1, Protease, MASLD, Hepatocyte lipid accumulation
Address and Contact Information 1 National Engineering Laboratory for Druggable Gene and Protein Screening, Northeast Normal University, Changchun 130117, China
2 China International Joint Research Center for Human Stem Cell Bank, Northeast Normal University, Changchun 130024, China
3 Key Laboratory of Molecular Epigenetics, Institute of Genetics and Cytology, Ministry of Education, Northeast Normal University, Changchun 130024, China
4 School of Life Sciences, Changchun Normal University, Changchun 130032, China
*Corresponding author: Shuyue Wang wangsy171@nenu.edu.cn Xiaoguang Yang yangxg168@nenu.edu.cn
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No.  29DOI: 10.1186/s11658-025-00851-2 Volume 31 (2026) - 30:29
Title SEPSIS ALTERS NK CELL TRANSCRIPTIONAL PROGRAMS FOR STRESS, ACTIN REMODELING, AND INTRACELLULAR TRAFFICKING
Authors Holger A. Lindner1*, Carolina de la Torre2, Sonia Y. Velásquez1, Jutta Schulte1, Carsten Sticht2, Manfred Thiel1 and Anna Coulibaly1*
Abstract Background: Natural killer (NK) cells exert cytotoxicity against transformed and infected cells. In human sepsis, a suppressive NK cell receptor signature and defective effector molecule expression have been described. However, the transcriptional mechanisms underlying this phenotype remain poorly defined.
Methods: We analyzed microarray-based transcriptomic profiles of isolated peripheral NK cells from patients with sepsis, patients with systemic inflammatory response syndrome (SIRS), and presurgical controls. Enrichment analyses of canonical pathways, biological processes, and cellular compartments were performed. Differential gene expression was validated in an independent cohort using a multiplex branched-DNA assay. Functional signal transducer and activator of transcription (STAT) phosphorylation responses ex vivo and proliferation marker expression were assessed by flow cytometry in independent patient samples.
Results: NK cells from patients with sepsis displayed transcriptional signatures indicative of DNA replication stress, endoplasmic reticulum (ER) stress, altered cytoskeletal dynamics, and vesicle trafficking. Despite enrichment of proliferation-associated transcriptional programs, NK cells showed no increase in Ki-67 expression, indicating impaired proliferative activity. In contrast, NK cells from patients with SIRS exhibited downregulation of immune signaling pathways.
Conclusion: This study identifies early stress-associated transcriptional programs and impaired subcellular organization in circulating NK cells during sepsis. Dysregulated DNA replication and ER stress responses, along with altered vesicle trafficking linked to impaired small guanosine triphosphatase (GTPase) signaling, may contribute to NK cell dysfunction in sepsis and may inform the development of NK cell-based immunotherapeutic strategies in critical illness.
Keywords Gene expression profiling, Natural killer cells, Pathway analysis, Sepsis, Systemic inflammatory response syndrome
Address and Contact Information 1 Department of Anesthesiology, Surgical Intensive Care Medicine and Pain Medicine, Mannheim Institute for Innate Immunoscience (MI3), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
2 NGS Core Facility, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
*Correspondence: Holger A. Lindner Holger.Lindner@medma.uni-heidelberg.de Anna Coulibaly Anna.Coulibaly@medma.uni-heidelberg.de
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No.  33DOI: 10.1186/s11658-026-00863-6 Volume 31 (2026) - 30:33
Title TRMT6/TRMT61A-MEDIATED tRNA m1A MODIFICATION ENHANCES PROTEIN TRANSLATION AND ACTIVATES THE IRE1α–XBP1s PATHWAY TO PROMOTE ANAPLASTIC THYROID CANCER PROGRESSION
Authors Ying Ding1,2, Ziyang Feng2,3, Guanjun Chen3, Yunqing Liu3, Yuxing Zhu3 and Ke Cao3*
Abstract Background: Anaplastic thyroid cancer (ATC) is a highly aggressive malignancy with rapid progression and poor prognosis. Although N1-methyladenosine (m1A) modification has been implicated in cancer development, the specific role of tRNA m1A modification in ATC remains unclear.
Methods: An integrated multi-omics approach is employed, including m1A-MAP-tRNA-seq, tRNA-seq, RNA-seq, and Ribo-seq, complemented by functional assays such as tRNA aminoacylation assay, puromycin intake assay, and L-HPG staining. Additional experiments involved polysome profiling qRT-PCR, codon-switch assay, endoplasmic reticulum (ER)-tracker and TPE-MI staining, transmission electron microscopy, ChIP-qPCR, dual-luciferase reporter assay, and BODIPY staining to elucidate the underlying mechanism.
Results: TRMT6/TRMT61A is significantly upregulated in ATC. The complex promotes tumor cell proliferation and metastasis by enhancing the aminoacylation of specific tRNAs, thereby facilitating global protein translation. Elevated translation led to the accumulation of unfolded proteins in the ER, which activates the IRE1α–XBP1s pathway. Notably, m1A modification also increased IRE1α translation, further amplifying the pathway. Activation of the IRE1α–XBP1s pathway upregulates DGAT1 expression, which promotes triglyceride synthesis.
Conclusions: Together, these findings reveal a previously unrecognized mechanism by which TRMT6/TRMT61A drives ATC progression through translational and metabolic reprogramming, identifying TRMT6/TRMT61A as a promising therapeutic target in ATC.
Keywords TRMT6/TRMT61A, tRNA, m1A modification, Translation, IRE1α–XBP1s
Address and Contact Information 1 Department of Breast Thyroid Surgery, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
2 Postdoctoral Station of Medical Aspects of Specific Environments, the Third Xiangya Hospital, Central South University, Changsha, China
3 Department of Oncology, Third Xiangya Hospital, Central South University, Changsha 410013, Hunan, China
*Correspondence: Ke Cao csucaoke@163.com
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No.  22DOI: 10.1186/s11658-026-00867-2 Volume 31 (2026) - 30:22
Title THE PROMOTING ROLES OF GLP1R AND GIPR IN STEMNESS MAINTENANCE AND MULTIPLE LINEAGE-SPECIFIC DIFFERENTIATION OF PDLSCs
Authors Yifen Shen1†, Mengjie Zhang3†, Tao Yang4, Yuxiang Wu5, Yinfeng Qiu6, Le Zhang2,7, Fei Li8, Minjie Chen3, Qili Chen9*, Wenbin Wei3*, Hua Li2,7* and Yihang Shen1*
Abstract Background: Periodontal ligament stem cells (PDLSCs) hold great promise for periodontal regeneration therapy. However, their self-renewal and multilineage differentiation capabilities are often compromised by adverse factors in the periodontal microenvironment. Therefore, identifying novel therapeutic targets and elucidating the underlying molecular mechanisms to protect the proliferative and differentiation potential of PDLSCs is of significant importance.
Methods: PDLSCs were exposed to electronic cigarette extract and various common oral stressors to evaluate the expression of glucagon such as peptide 1 receptor (GLP1R) and gastric inhibitory polypeptide receptor (GIPR). PDLSCs isolated from patients with periodontitis and PDLSCs from a mouse periodontitis model were also analyzed. Functional studies were performed by GLP1R or GIPR knockdown, overexpression, and treatment with single or dual receptor agonists, followed by assessment of cell proliferation and multilineage differentiation capacities. Transcriptome (RNA-seq), chromatin immunoprecipitation sequencing (ChIP-seq), and RNA immunoprecipitation sequencing (RIP-seq) were applied to delineate downstream signaling pathways and RNA–protein interactions. Protein synthesis regulation was further investigated by immunoprecipitation of interferon induced protein with tetratricopeptide repeats (IFIT)-associated translation initiation factors. For in vivo validation, wild-type and GLP1R/GIPR double-knockout periodontitis mice were transplanted with CRISPR-Cas9 mCherry-labeled PDLSCs and treated with receptor agonists. Disease severity and PDLSC fate were evaluated by histology and lineage tracing. Finally, a questionnaire-based survey was conducted in 150 patients with periodontitis, including 74 individuals with long-term use (> 1 month) of GLP1R or GLP1R/GIPR dual agonists (e.g., semaglutide, liraglutide, tirzepatide), to assess their periodontal outcomes.
Results: GLP1R and GIPR expression were markedly downregulated in PDLSCs exposed to multiple stressors and in PDLSCs isolated from periodontitis specimens. RNA-seq, ChIP-seq, and RIP-seq identified downstream pathways and RNA–protein interactions implicated in receptor-mediated regulation. Functionally, GIPR agonism promoted PDLSC proliferation via activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) pathway, whereas GLP1R agonist enhanced multilineage differentiation capacity in vitro. Mechanistically, GLP1R knockdown induced robust upregulation of IFIT1/2/3, while GLP1R agonist suppressed IFIT expression. IFIT1/2/3 were shown to interact with eIF3C and to inhibit translation of differentiation-related mRNAs, linking GLP1R signaling to translational control of PDLSC fate. In vivo, transplantation experiments in both wild-type and GLP1R/GIPR double-knockout periodontitis mice demonstrated that single and dual receptor agonists significantly improved endogenous and exogenous PDLSC-mediated periodontal regeneration. Consistently, a clinical survey of 150 patients with periodontitis (74 receiving GLP1R or dual agonists) revealed significantly better periodontal staging and grading in treated individuals, with longer agonist exposure associated with greater improvement.
Conclusions: Our findings uncover the different molecular roles of GIPR and GLP1R in self-renewal capacity and multipotency of PDLSCs, and open new avenues for developing therapeutic targets and strategies in oral tissue engineering and regenerative medicine.
Keywords PDLSC, GLP1R, GIPR, MAPK/ERK, IFIT
Address and Contact Information Central Laboratory, Suzhou Ninth People’s Hospital, Soochow University, 2666 Ludang Road, Suzhou 215200, Jiangsu, China
2 Jiangsu Province Engineering Research Center of Development and Translation of Key Technologies for Chronic Disease Prevention and Control, Suzhou Vocational Health College, 28 Kehua Road, Suzhou 215009, Jiangsu, China
3 Department of Oral Surgery, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People’s Hospital; National Center for Stomatology, and National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Shanghai 200023, China
4 Department of Medical Cosmetology, Suzhou Ninth People’s Hospital, Soochow University, Suzhou 215200, Jiangsu, China
5 Department of Pathology, Suzhou Ninth People’s Hospital, Soochow University, Suzhou 215200, Jiangsu, China
6 Department of Stomatology, Suzhou Ninth People’s Hospital, Soochow University, Suzhou 215200, Jiangsu, China
7 Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
8 Department of Preventive Dentistry, Shanghai Jiao Tong University School of Medicine Affiliated Ninth People’s Hospital; National Center for Stomatology, and National Clinical Research Center for Oral Diseases; Shanghai Key Laboratory of Stomatology; Shanghai Research Institute of Stomatology, 639 Zhizaoju Road, Shanghai 200023, China
9 School of Pharmacy, China Medical University, 77 Puhe Road, Shenyang 110122, Liaoning, China
*Corresponding author: Qili Chen qlchen@cmu.edu.cn Wenbin Wei tian_qian_cool@126.com Hua Li kaikaixinxin@sjtu.edu.cn Yihang Shen devbrother@sjtu.edu.cn
† Yifen Shen and Mengjie Zhang have contributed equally to this work.
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No.  34DOI: 10.1186/s11658-026-00875-2 Volume 31 (2026) - 30:34
Title BIP ORCHESTRATES BIDIRECTIONAL ER PROTEIN TRAFFICKING VIA CO-CHAPERONE COMPLEXES
Authors Suma Biadsy1, Ayelet Gilad1, Laila Abu Madegam1 and Aeid Igbaria1*
Abstract Background: Interorganellar protein redistribution is an emerging but underexplored aspect of proteostasis and cellular adaptation. Beyond canonical transcriptional and translational regulation, cells dynamically reprogram the spatial distribution of proteins to rapidly respond to environmental stress. This spatial plasticity enables single gene products to acquire novel, context-dependent functions on the basis of subcellular localization. Such relocalization is particularly pronounced in pathological conditions, such as cancer and viral infections, where proteome remodeling enhances cellular survival and adaptability. We previously defined endoplasmic reticulum (ER)-to-cytosol signaling (ERCYS) as a stress-responsive mechanism that alleviates ER burden by redistributing proteins into the cytosol. Despite growing interest, the molecular mechanisms driving ERCYS and related forms of spatial proteome remodeling remain poorly defined. Methods: To investigate these mechanisms, we employed siRNA- and CRISPR-based depletion of BIP, SGTA, and DNAJB12/14, coupled with subcellular fractionation and immunoblotting to assess protein localization under stress. Co-immunoprecipitation was used to examine protein–protein interactions, and unfolded protein response (UPR) activation was quantified via quantitative reverse transcription polymerase chain reaction (RT-qPCR). Results: Our results reveal a previously unrecognized role for the UPR in mediating ER protein reflux. Specifically, we show that ATF6 and IRE1, but not PERK, are essential for initiating ERCYS. Notably, IRE1 simultaneously promotes ERCYS while suppressing BAX/BAK-mediated ER membrane permeabilization. Furthermore, we uncover a noncanonical, signaling-independent function of the ER-resident chaperone BIP in protein reflux. BIP forms a complex with membrane-bound DNAJB12/14 and cytosolic SGTA, facilitating chaperone-guided export of proteins from the ER lumen. This process depends on an intact DNAJB12 J-domain and requires BIP to originate within the ER, supporting a directional, regulated export mechanism. These findings challenge the classical view of BIP as solely mediating inward translocation and reveal a bidirectional role in protein trafficking. Our work uncovers a novel layer of UPR-regulated spatial proteome remodeling with potential relevance in cancer biology.
Keywords Spatial proteome, UPR, ER stress, Cancer, DNAJB12, ERCYS
Address and Contact Information 1 Department of Life Sciences, Ben-Gurion University of the Negev, Beer Sheva, Israel
*Corresponding author: Aeid Igbaria aigbaria@bgu.ac.il
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No.  35DOI: 10.1186/s11658-026-00865-4 Volume 31 (2026) - 30:35
Title EXTRACHROMOSOMAL CIRCULAR DNA: A POTENTIAL CLINICAL THERAPEUTIC TARGET IN MALIGNANT TUMORS
Authors Hao Zhang1,2, Enqing Zhuo4, Meng Li1, Junxiao Feng3, Xingjuan Shi3* and Xiaoou Sun1*
Abstract Malignant tumors, commonly referred to as cancer, are pathological conditions distinguished by the unregulated growth and infiltration of malignant cells into adjacent tissues or remote organs. This uncontrolled cell proliferation results in continuous tumor cell division and proliferation in the body. The tumor invades surrounding tissues and spreads to other body parts through the bloodstream or lymphatic system. This forms distant metastases that can influence several systems and organs, seriously affecting the health and life of patients. Effective treatment methods are still lacking owing to their complex mechanism of action. With the continuous development of precision medicine, research on the correlation between extrachromosomal circular DNA (eccDNA) and malignant tumors has become a hot topic. The eccDNA is a circular DNA molecule independent of chromosomes, more stable, and less susceptible to nuclease degradation. Increasing evidence has shown that eccDNA has a function in malignant tumor heterogeneity, invasiveness, evolution, and chemical resistance. It drives tumor heterogeneity so that cancer cells can quickly adapt to treatment plans and environmental changes. Compared with linear chromosomal DNA, eccDNA has an open structure, carries active histone modifications, and can facilitate long-range gene interactions, significantly improving the transcriptional activity of genes and playing an essential regulatory role in disease progression. It also serves as a biological marker for diagnosing and predicting malignant tumors, thus attracting increasing attention. This article reviews its role, mechanism, and value in malignant tumors, providing a new perspective for diagnosing and treating this disease.
Keywords Extrachromosomal circular DNA, Malignant tumor, Regulatory effect, Biomarker
Address and Contact Information 1 Institute of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
2 Guangzhou Huateng Bioscience Corporation, Guangzhou 510530, China
3 School of Life Science and Technology, Key Laboratory of Developmental Genes and Human Disease, Southeast University, Nanjing 210096, China
4 Department of 2nd Oncology, Guangdong Second Provincial General Hospital, Guangzhou, Guangdong, China
*Corresponding author: Xingjuan Shi xingjuanshi@seu.edu.cn Xiaoou Sun xiaoousun@gdut.edu.cn
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No.  36DOI: 10.1186/s11658-025-00849-w Volume 31 (2026) - 30:36
Title SPATIOTEMPORAL DYNAMICS OF REACTIVE OXYGEN SPECIES: IMPLICATIONS FOR CELLULAR HOMEOSTASIS AND REDOX THERAPIES
Authors Yucen Li1,2, Qiao Zhao3, Hanyu Hu1 and Jian-Fei Pei1*
Abstract Reactive oxygen species (ROS) are endogenously generated during cellular metabolism but can also be induced by environmental stressors, such as radiation, pollutants, and inflammation. While ROS are essential for cellular function, excessive levels of ROS can inflict damage on DNA, proteins, and lipids, resulting in cellular impairment and, in severe cases, cell death. Notably, both basal ROS levels and homeostatic set point of ROS vary markedly among various subcellular compartments, with each organelle exhibiting distinct pathological consequences when its oxidative homeostasis is disrupted. Furthermore, ROS levels exhibit significant diurnal oscillations in many species, resulting in dynamic changes in cellular redox homeostasis over the 24-h cycle. Regrettably, these spatiotemporal dimensions of ROS regulation have often been overlooked in previous studies and are rarely considered in current antioxidant therapeutic strategies. This review provides a comprehensive overview of the major sites of ROS and the enzymes responsible for ROS generation and scavenging in different subcellular locations, along with their temporal variations. Additionally, the driving forces and biological functions of redox rhythms are also discussed. By integrating these insights, we aim to advance the understanding of spatiotemporal ROS regulation and provide a foundation for developing precision redox-based therapies with enhanced clinical translation.
Keywords Oxidative stress, Circadian rhythms, Redox precision therapies, ROS spatiotemporal regulation
Address and Contact Information 1 Department of Medical Genetics, Key Laboratory of Cell Biology, Ministry of Public Health, and Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
2 Department of Pathogen Biology, College of Basic Medical Sciences, China Medical University, Shenyang, China
3 Department of Internal Medicine (Nephrology) and the Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
*Corresponding author: Jian-Fei Pei jamffypei@163.com
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No.  25DOI: 10.1186/s11658-026-00878-z Volume 31 (2026) - 30:25
Title CORRECTION: THE DIRECT BINDING OF BIOACTIVE PEPTIDE ANDERSONIN‐W1 TO TLR4 EXPEDITES THE HEALING OF DIABETIC SKIN WOUNDS
Authors Chao Li3†, Yuxin Xiong1,4†, Zhe Fu1†, Yuxin Ji1, Jiayi Yan1, Yan Kong1, Ying Peng1, Zeqiong Ru1, Yubing Huang3, Yilin Li1, Ying Yang4*, Li He5*, Jing Tang3*, Ying Wang2* and Xinwang Yang1*
Abstract Correction: Cellular & Molecular Biology Letters (2024) 29:24
https://doi.org/10.1186/s11658-024-00542-4

In this article [1], the wrong figure appeared as Fig. 1, S5 and S6; the correct figures should have appeared as shown below.
Keywords
Address and Contact Information 1 Department of Anatomy and Histology & Embryology, Faculty of Basic Medical Science, Kunming Medical University, Yunnan 650500, Kunming, China
2 Key Laboratory of Chemistry in Ethnic Medicinal Resources & Key Laboratory of Natural Products Synthetic Biology of Ethnic Medicinal Endophytes, State Ethnic Affairs Commission & Ministry of Education, School of Ethnic Medicine, Yunnan Minzu University, Yunnan 650504, Kunming, China
3 Department of Biochemistry and Molecular Biology, Faculty of Basic Medical Science, Kunming Medical University, Yunnan 650500, Kunming, China
4 Department of Endocrinology, Affiliated Hospital of Yunnan University, Yunnan 650021, Kunming, China
5 Department of Dermatology, First Affiliated Hospital of Kunming Medical University, Yunnan 650032, Kunming, China
*Corresponding author: Ying Yang yangying2072@126.com Li He drheli2662@126.com Jing Tang gracett916@163.com Ying Wang wangying_814@163.com Xinwang Yang yangxinwanghp@163.com; yangxinwang@kmmu.edu.cn
† Chao Li, Yuxin Xiong and Zhe Fu contributed equally to this manuscript.
The original article can be found online at https://doi.org/10.1186/s11658-024-00542-4.
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No.  38DOI: 10.1186/s11658-026-00862-7 Volume 31 (2026) - 30:38
Title BANNAKUNIN: A DUAL-TARGET KUNITZ INHIBITOR BRIDGING ANTICOAGULATION (FXa/XIIa) AND ANTI-PLATELET (α2β1/P2Y12) PATHWAYS
Authors Miao He1†, Yanmei He1†, Xiaoli Feng1†, Zhuorui Li1, Ting Lin1, Jiayi Yang1, Haiyan Luo1, Lixian Mu1*, Hailong Yang1,2* and Jing Wu1*
Abstract Background: Thrombosis is a major cause of morbidity and mortality worldwide. Consequently, there is an ongoing search for efficacious and safe anti-thrombotic drugs. Haematophagous animals have developed a large variety of salivary bioactive components to counteract host haemostatic responses. We aim to discover anti-thrombotic agents with dual anti-platelet and anticoagulant activities.
Methods: A novel single Kunitz domain inhibitor (Bannakunin) precursor cloned from the salivary glands complementary DNA (cDNA) library of blood-sucking black fly Simulium bannaense was expressed in Escherichia coli. Recombinant Bannakunin was purified by Immobilised Metal Affinity Chromatography and High-Performance Liquid Chromatography. The secondary structure was determined by circular dichroism spectroscopy. The anti-thrombotic activity was evaluated through carotid artery thrombosis and tail vein thrombosis models. The inhibitory activity was evaluated using serine protease inhibition assays, SPR and molecular docking. The regulation on platelets was assessed by platelet aggregation, clot retraction and platelet spreading assays. Subsequently, its target receptors and signalling pathways were investigated through western blotting, enzyme-linked immunosorbent assay (ELISA) and flow cytometry.
Results: Recombinant Bannakunin demonstrated significant anti-thrombotic efficacy in murine FeCl3-induced carotid artery and carrageenan-induced tail vein thrombosis models and did not induce bleeding complications. Simultaneously, Bannakunin markedly prolonged prothrombin time (PT) and activated partial thromboplastin time (aPTT) in human plasma. Further investigation revealed that Bannakunin could inhibit the activity of the coagulation factors FXa and FXIIa, as well as the activities of elastase, trypsin, and plasma kallikrein, but it did not inhibit thrombin and FXIa. Surface plasmon resonance studies have shown that Bannakunin binds to the active sites of human elastase (KD: 1.95 nM) and human FXa (KD: 42.9 nM) with the highest affinity. Intriguingly, we observed that Bannakunin significantly inhibited clot retraction, as well as platelet aggregation and spreading. Mechanistically, Bannakunin inhibited collagen-induced platelet activation by downregulating the integrin α2β1-mediated Src/Syk/PLCγ2 signalling pathway and the release of Ca2+, TXB2 and ATP. Furthermore, Bannakunin could effectively inhibit ADP-induced platelet activation through blocking P2Y12 receptor, decreasing the activation of PI3K/Akt signalling pathways and upregulating the level of cAMP.
Conclusions: These findings enrich our understanding of the anti-platelet functions of Kunitz-type inhibitors and position Bannakunin as a promising molecular template for the development of novel anti-thrombotic drugs.
Keywords Kunitz-type inhibitor, Anti-thrombotic, Anticoagulation, Anti-platelet
Address and Contact Information 1 School of Basic Medical Sciences, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming 650500, Yunnan, China
2 Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, School of Rehabilitation, Kunming Medical University, 1168 West Chunrong Road, Yuhua Avenue, Chenggong District, Kunming 650500 Yunnan, China
*Corresponding author: Lixian Mu mulixian77@163.com Hailong Yang jxauyhl@163.com Jing Wu wujing_205@163.com
† Miao He, Yanmei He, Xiaoli Feng contributed equally to this work.
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