Journal of Molecular Cell Biology最新文献

TUBA8 promotes neuronal dendrite development through its 40th alanine. TUBA8通过其40号丙氨酸促进神经元树突发育。

IF 5.9 2区生物学

Journal of Molecular Cell Biology Pub Date : 2025-10-17 DOI: 10.1093/jmcb/mjaf036

Fengxia Shao, Huaqing Xue, Boran Chang, Yanling Liu, Suhao Cao, Jinsong Li, Xu Zhang, Lei Diao, Lan Bao

{"title":"TUBA8 promotes neuronal dendrite development through its 40th alanine.","authors":"Fengxia Shao, Huaqing Xue, Boran Chang, Yanling Liu, Suhao Cao, Jinsong Li, Xu Zhang, Lei Diao, Lan Bao","doi":"10.1093/jmcb/mjaf036","DOIUrl":"https://doi.org/10.1093/jmcb/mjaf036","url":null,"abstract":"The functional specificity of tubulin isotypes has been demonstrated by various neurological diseases caused by an increasing number of mutations in tubulin isotypes. TUBA8 is specifically localized in cerebellar Purkinje cells, which exhibit the most elaborate dendritic trees in the central nervous system. However, the role and related molecular mechanism of TUBA8 in regulating neuronal dendritic morphology remain poorly understood. Here, we report that TUBA8 is required for neuronal dendrite development. As the most divergent member in α-tubulin isotypes, the expression of TUBA8 in Purkinje cells starts at P0, plateaus at P10 and sustains into adulthood. Loss of TUBA8 in Purkinje cells induces global dendritic height defects in multiple lobules during development and aging. Meanwhile, TUBA8 deficiency causes age-dependent decreased locomotor activity and anxiety-like behavior. In contrast to TUBA8, TUBA4A, another tubulin isotype highly expressed in Purkinje cells, is not required for dendrite development. Furthermore, the 40th alanine, which differs with any other α-tubulin isotype and cannot be modified by acetylation, methylation or lactylation, mediates the promoting effect of TUBA8 in neuronal dendrite development. This study reveals a specific role of TUBA8 in regulating neuronal dendritic morphology and highlights the importance of 40th amino acid in implementing functions of α-tubulin isotypes.","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-10-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145308254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

APP ubiquitination by VHL protein is essential for MVB sorting and lysosomal degradation. APP被VHL蛋白泛素化是MVB分选和溶酶体降解所必需的。

IF 5.9 2区生物学

Journal of Molecular Cell Biology Pub Date : 2025-10-07 DOI: 10.1093/jmcb/mjaf033

Chunyan Shan, Rixu Cong, Xiangyu Xu, Yuanjun Li, Yonglu Tian, Wenyuan Cao, Wei Zhao, Linqing Miao, Junlin Teng, Ning Huang, Jianguo Chen

{"title":"APP ubiquitination by VHL protein is essential for MVB sorting and lysosomal degradation.","authors":"Chunyan Shan, Rixu Cong, Xiangyu Xu, Yuanjun Li, Yonglu Tian, Wenyuan Cao, Wei Zhao, Linqing Miao, Junlin Teng, Ning Huang, Jianguo Chen","doi":"10.1093/jmcb/mjaf033","DOIUrl":"https://doi.org/10.1093/jmcb/mjaf033","url":null,"abstract":"Amyloid precursor protein (APP), a type I transmembrane protein, is closely related to the pathogenesis of Alzheimer's disease (AD). Amyloid beta (Aβ) is generated by sequential processing of APP in the Golgi apparatus and endosomes, and its toxicity leads to neuron dysfunction and neurodegeneration. APP is selectively shuttled between intracellular membrane compartments and ultimately transported into lysosomes. However, the mechanisms underlying APP sorting signals and lysosomal degradation are largely unclear. In this study, we show that the von Hippel‒Lindau protein (VHL), a subunit of an E3 ligase, recognizes the cytoplasmic domain of APP and mediates its ubiquitination. VHL-mediated ubiquitination facilitates the sorting of membrane APP into intraluminal vesicles of multivesicular bodies (MVBs) and subsequent degradation in lysosomes. Therefore, the loss of VHL accelerates Aβ plaque deposition and memory deficits in AD model mice. Our findings reveal the role of VHL in restricting AD pathogenesis through ubiquitination-dependent MVB sorting and lysosomal degradation of APP.","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145238843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Regulated cell death in organ transplantation: Recent developments and mechanistic overview. 器官移植中受调控的细胞死亡：最新进展和机制综述。

IF 5.9 2区生物学

Journal of Molecular Cell Biology Pub Date : 2025-09-24 DOI: 10.1093/jmcb/mjaf034

Qian Chen, Jiashi Sun, Shifan Zhu, Minghui Wu, Hakjun Lee, Azeem Alam, Moradi Kimia, Enqiang Chang, Hailin Zhao, Yue Jin, Daqing Ma

{"title":"Regulated cell death in organ transplantation: Recent developments and mechanistic overview.","authors":"Qian Chen, Jiashi Sun, Shifan Zhu, Minghui Wu, Hakjun Lee, Azeem Alam, Moradi Kimia, Enqiang Chang, Hailin Zhao, Yue Jin, Daqing Ma","doi":"10.1093/jmcb/mjaf034","DOIUrl":"https://doi.org/10.1093/jmcb/mjaf034","url":null,"abstract":"Organ transplantation is a definitive therapeutic option for patients with end-stage organ dysfunction and failure. Ischaemia-reperfusion (IR) injury is one of the leading causes of low graft utilisation as it significantly increases the risk of primary graft dysfunction and acute rejection following transplantation. This risk is particularly high for organs obtained from donors after circulatory death (DCD) when compared with the donors from brain death (DBD). IR injury exacerbates tissue damage via various mechanisms including the induction of regulated cell death. Regulated cell death and its consequences play critical roles in determining graft survival and function, thereby influencing the overall success of the transplant. Understanding the mechanisms underlying regulated cell death in IR injury is essential for developing therapeutic strategies to minimise tissue damage and improve clinical outcomes in organ transplantation. This review mainly discussed different types of regulated cell death and underlying mechanisms towards preventive cell death strategies in DBD and DCD organ transplantation in preclinical settings.","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145131227","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

The tumor-associated fibroblasts regulate urothelial carcinoma progression. 肿瘤相关成纤维细胞调节尿路上皮癌的进展。

IF 5.9 2区生物学

Journal of Molecular Cell Biology Pub Date : 2025-09-19 DOI: 10.1093/jmcb/mjaf032

Yu Xiao, Junfeng Yang, Mengjie Sun, Yongfu Li, Qinyin Liu, Jinjun Leng, Maolin Yang, Jinrui Wang, Hongju Li, Caifeng Yang, Changfen Luo, Jiahong Li, Longli Kang, Fen Huang, Yanhong Yu, Chuanmao Zhang

{"title":"The tumor-associated fibroblasts regulate urothelial carcinoma progression.","authors":"Yu Xiao, Junfeng Yang, Mengjie Sun, Yongfu Li, Qinyin Liu, Jinjun Leng, Maolin Yang, Jinrui Wang, Hongju Li, Caifeng Yang, Changfen Luo, Jiahong Li, Longli Kang, Fen Huang, Yanhong Yu, Chuanmao Zhang","doi":"10.1093/jmcb/mjaf032","DOIUrl":"https://doi.org/10.1093/jmcb/mjaf032","url":null,"abstract":"Tumor-associated fibroblasts (CAFs) regulate tumorigenesis, tumor cell proliferation, and metastasis via secreting related regulatory factors; however, the evidence for CAFs in regulating development of upper tract urothelial carcinoma (UTUC) remains unclear. Here, by utilizing single-cell RNA sequencing (scRNA-seq), single-nucleus RNA sequencing (snRNA-seq), SpaTial enhanced resolution omics-sequencing (Stereo-seq), and UTUC immunofluorescence chip cohort to construct the first comprehensive microenvironmental atlas of CAFs, we investigated the roles of CAFs in UTUC progression. Through hierarchical clustering and the copy number variation (CNV) scores of UTUC epithelial cells, we first classified tumor epithelial cells into high-malignant, medium-malignant, and low-malignant potential categories. We found that the myofibroblastic CAFs1 (myCAFs1) and myCAFs2 subclusters exhibited significant interaction signals with all three types of epithelial cells, among which high-malignant epithelial cells (HMECs) exhibited pronounced communication signals with CAFs, and FN1 and COL1A1 generated by CAFs played critical roles in this process, suggesting that the progression of UTUC may be attributed to the activation of tumor cells by CAFs. Both myCAFs1 and myCAFs2 simultaneously affect bladder urothelial carcinoma (BUC) prognosis, with the risk model showing good consistency across cohorts. The study constructs a multi-omics landscape of UTUC and identify common prognostic markers shared with BUC.","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145091953","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Automating classification of treatment responses to combined targeted therapy and immunotherapy in HCC. 肝癌联合靶向治疗和免疫治疗治疗反应的自动分类。

IF 5.9 2区生物学

Journal of Molecular Cell Biology Pub Date : 2025-09-17 DOI: 10.1093/jmcb/mjaf031

Bing Quan, Mingrong Dai, Peiling Zhang, Shiping Chen, Jialiang Cai, Yujie Shao, Pengju Xu, Peizhao Li, Lei Yu

{"title":"Automating classification of treatment responses to combined targeted therapy and immunotherapy in HCC.","authors":"Bing Quan, Mingrong Dai, Peiling Zhang, Shiping Chen, Jialiang Cai, Yujie Shao, Pengju Xu, Peizhao Li, Lei Yu","doi":"10.1093/jmcb/mjaf031","DOIUrl":"https://doi.org/10.1093/jmcb/mjaf031","url":null,"abstract":"Tyrosine kinase inhibitors (TKIs) combined with immunotherapy regimens are now widely used for treating advanced hepatocellular carcinoma (HCC), but their clinical efficacy is limited to a subset of patients. Considering that the vast majority of advanced HCC patients lose the opportunity for liver resection and thus cannot provide tumor tissue samples, we leveraged the clinical and image data to construct a multimodal convolutional neural network (CNN)-Transformer model for predicting and analyzing tumor response to TKI-immunotherapy. An automatic liver tumor segmentation system, based on a two-stage 3D U-Net framework, delineates lesions by first segmenting the liver parenchyma and then precisely localizing the tumor. This approach effectively addresses the variability in clinical data and significantly reduces bias introduced by manual intervention. Thus, we developed a clinical model using only pre-treatment clinical information, a CNN model using only pre-treatment magnetic resonance imaging data, and an advanced multimodal CNN-Transformer model that fused imaging and clinical parameters using a training cohort (n = 181) and then validated them using an independent cohort (n = 30). In the validation cohort, the area under the curve (95% confidence interval) values were 0.720 (0.710-0.731), 0.695 (0.683-0.707), and 0.785 (0.760-0.810), respectively, indicating that the multimodal model significantly outperformed the single-modality baseline models across validations. Finally, single-cell sequencing with the surgical tumor specimens reveals tumor ecosystem diversity associated with treatment response, providing a preliminary biological validation for the prediction model. In summary, this multimodal model effectively integrates imaging and clinical features of HCC patients, has a superior performance in predicting tumor response to TKI-immunotherapy, and provides a reliable tool for optimizing personalized treatment strategies.","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145092000","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Combination therapy dramatically promotes remyelination. 联合治疗可显著促进髓鞘再生。

IF 5.9 2区生物学

Journal of Molecular Cell Biology Pub Date : 2025-09-10 DOI: 10.1093/jmcb/mjaf005

Yawen Li, Pingping Li, Yixuan Song, Wenjun Zhang, Xinyue Jiang, Siyi Chen, Wei Luo, Caiyun Ma, Changqing Liu, Jianguo Niu, Aibin Liang, Yarui Du, Bo O Zhou, Mingliang Zhang

{"title":"Combination therapy dramatically promotes remyelination.","authors":"Yawen Li, Pingping Li, Yixuan Song, Wenjun Zhang, Xinyue Jiang, Siyi Chen, Wei Luo, Caiyun Ma, Changqing Liu, Jianguo Niu, Aibin Liang, Yarui Du, Bo O Zhou, Mingliang Zhang","doi":"10.1093/jmcb/mjaf005","DOIUrl":"10.1093/jmcb/mjaf005","url":null,"abstract":"Multiple sclerosis (MS) is an immune-mediated disease in the central nervous system that is characterized by demyelination, axonal degeneration, and progressive neurological disability and is so far incurable. Current medications are predominantly immune-targeted but fail to prevent disease progression due to their inability to actively promote remyelination. Small molecules have been reported to promote myelin regeneration but their therapeutic efficacy is limited by insufficient immune modulation. Thus, the strategies achieving both immunomodulation and active myelin regeneration are highly desired. Here, we investigated a combination therapy (CT) for MS designed to simultaneously modulate immune responses and promote oligodendrocyte precursor cell differentiation and in situ remyelination in an experimental autoimmune encephalomyelitis mouse model. Remarkably, CT suppressed acute inflammatory activity, activated the signaling pathways for myelin development, induced the expression of myelin-related genes, and significantly promoted remyelination and the recovery of motor performance. Furthermore, a reduced immunomodulator dosage or shorter treatment duration with small-molecule drugs achieved comparable symptom reversal. Our findings demonstrate the potential of CT to address complex pathobiology and lay a foundation for developing novel therapeutic strategies for MS.","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12421577/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143557192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A nomogram to predict gestational diabetes mellitus: a multicenter retrospective study. 预测妊娠期糖尿病的nomogram：一项多中心回顾性研究。

IF 5.9 2区生物学

Journal of Molecular Cell Biology Pub Date : 2025-09-10 DOI: 10.1093/jmcb/mjaf008

Rui Zhang, Zhangyan Li, Nuerbiya Xilifu, Mengxue Yang, Yongling Dai, Shufei Zang, Jun Liu

{"title":"A nomogram to predict gestational diabetes mellitus: a multicenter retrospective study.","authors":"Rui Zhang, Zhangyan Li, Nuerbiya Xilifu, Mengxue Yang, Yongling Dai, Shufei Zang, Jun Liu","doi":"10.1093/jmcb/mjaf008","DOIUrl":"10.1093/jmcb/mjaf008","url":null,"abstract":"While gestational diabetes mellitus (GDM) poses great threat to the health of mothers and children, there is no standard early prediction model for this disease yet. This study developed and evaluated a nomogram for predicting GDM in early pregnancy. Overall, 1824 pregnant women were randomly divided into the training and internal validation sets in the ratio of 7:3, with additional 1604 pregnant women for external validation. Multivariate logistic regression analysis was used to develop a prediction model for GDM, and a nomogram was utilized for model visualization. Risk factors in the prediction model involved age, pre-pregnancy body mass index, reproductive history, family history of diabetes, creatinine level, triglyceride level, low-density lipoprotein level, neutrophil count, and monocyte count. Model performance was evaluated using receiver operating characteristic (ROC) curves, calibration curves, and decision clinical analysis (DCA). The area under ROC curve (AUC) value of the model was 0.804 for the training set, and similar AUC values were obtained for the internal (0.800) and external (0.829) validation sets, verifying the stability of the model. The calibration curves showed that the probabilities of GDM predicted by the nomogram highly correlated with the observed frequency values. The DCA curves indicated that the prediction model is clinically useful, thus potentially aiding early pregnancy management in women.","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12448233/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143597239","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Characterization of the nucleolar localization signal of TRMT10A and its importance for the m1G9 methylation of tRNAs in mammalian cells. 哺乳动物细胞中TRMT10A核仁定位信号的表征及其对trna m1G9甲基化的重要性

IF 5.9 2区生物学

Journal of Molecular Cell Biology Pub Date : 2025-09-10 DOI: 10.1093/jmcb/mjaf011

Tianyang Luo, Zhiyuan Shi, Haibin Yang, Jiafan Miao, Zilong Chang, Jie Zou, Qiang Zeng, Wenbin Wu, Yanan Jiang, Xiaoling Xie, Liu Cao, Hong Peng, Chunmei Li, Deyin Guo, Junyu Wu

引用次数: 0

Silencing GGH induces autophagy by increasing folate stress and production of NADH. 沉默GGH通过增加叶酸应激和NADH的产生诱导自噬。

IF 5.9 2区生物学

Journal of Molecular Cell Biology Pub Date : 2025-09-10 DOI: 10.1093/jmcb/mjaf014

Yu Li, Yuhui Du, Sijie Chen, Zhangrong Xie, Xinrui Li, Baoyue Lin, Zhiqing Zhou, Huijie Zhao, Guoan Chen

{"title":"Silencing GGH induces autophagy by increasing folate stress and production of NADH.","authors":"Yu Li, Yuhui Du, Sijie Chen, Zhangrong Xie, Xinrui Li, Baoyue Lin, Zhiqing Zhou, Huijie Zhao, Guoan Chen","doi":"10.1093/jmcb/mjaf014","DOIUrl":"10.1093/jmcb/mjaf014","url":null,"abstract":"There is an inextricable link between metabolic disorders and autophagy. Gamma-glutamyl hydrolase (GGH) is a lysosomal glycoprotein that reduces intracellular folate stress by catalyzing the hydrolysis of polyglutamylated folate into transportable monoglutamate. The relationship between folate metabolism, involving the folate metabolic enzyme GGH, and autophagy has rarely been reported. In this study, we found that GGH functions as a crucial oncogene in lung adenocarcinomas. Importantly, we found that cell autophagy and autophagic cell death are induced by GGH silencing through the elevated folate stress resulting from folate metabolism and the folate metabolite nicotinamide adenine dinucleotide (NADH). By increasing the NADH/NAD+ ratio, silencing GGH activates adenosine monophosphate-activated protein kinase (AMPK) through the activation of LKB1 and CAMKK2, as well as enhanced AMP/ATP and ADP/ATP ratios, which then triggers the initiation of early autophagy, finally resulting in autophagic cell death. Taken together, our study suggests that GGH may not only serve as a prognostic marker but also play a critical role in the initiation of early autophagy. Interventions targeting GGH to regulate folate metabolism and the proportion of NADH/NAD+ may have translational potential for precision therapy in human cancer.","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12527274/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144014701","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

AMPK maintains the activation of hepatic stellate cells through mitophagy-induced metabolic reprogramming. AMPK通过线粒体自噬诱导的代谢重编程维持肝星状细胞的激活。

IF 5.9 2区生物学

Journal of Molecular Cell Biology Pub Date : 2025-09-04 DOI: 10.1093/jmcb/mjaf030

Hanmin Wang, Guanzhen Wang, Tao Yin, Hao Li, Hanlin Wang, Yikai Shao, Yuanyuan Li, Rong Hua, Jia Li, Yi Zang

{"title":"AMPK maintains the activation of hepatic stellate cells through mitophagy-induced metabolic reprogramming.","authors":"Hanmin Wang, Guanzhen Wang, Tao Yin, Hao Li, Hanlin Wang, Yikai Shao, Yuanyuan Li, Rong Hua, Jia Li, Yi Zang","doi":"10.1093/jmcb/mjaf030","DOIUrl":"https://doi.org/10.1093/jmcb/mjaf030","url":null,"abstract":"The activation of hepatic stellate cells (HSCs), characterized by transdifferentiation from a quiescent state to a fibrogenic phenotype, is a core process of liver fibrosis. The metabolic reprogramming of HSCs plays a major role in this process to meet the high energy demands of myofibroblastic HSCs with multiple functions, such as extracellular matrix synthesis, migration, and proliferation. AMP-activated protein kinase (AMPK) is a gatekeeper of intracellular energy homeostasis, but its role in the activation of HSCs and the progression of liver fibrosis remains unclear. Here, we found that the phosphorylation of AMPK in HSCs was upregulated in liver tissues from metabolic dysfunction-associated steatohepatitis patients and from mice treated with carbon tetrachloride (CCl4) or bile duct ligation (BDL). HSC-specific deletion of two catalytic α-subunits of AMPK attenuated liver fibrosis in the CCl4 or BDL mouse model. In vitro analysis demonstrated that AMPK promoted HSC activation when challenged with various profibrogenic stimuli. The activation of AMPKα-deficient HSCs was impaired due to the decreased mitochondrial oxidative phosphorylation but restored after treatment with the mitophagy inducer rapamycin. Mechanistically, both the AMPK-ULK1 and AMPK-Raptor pathways contribute to the maintenance of the mitophagy pathway and mitochondrial quality. These findings provide direct evidence of the crucial role of AMPK-mitophagy signaling in ensuring mitochondrial health and sufficient energy supply during HSC activation. In this study, AMPK was modulated in HSCs prior to activation, which is distinguished from previous investigations and thus provides new insights into the role of AMPK during distinct phases of HSC activation.","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2025-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144992491","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0