Journal of Molecular Cell Biology最新文献

{"title":"Sarm1-containing extrachromosomal circular DNA promotes aging-associated cardiac fibrosis via TGF-β/Smad activation.","authors":"Ying Zhang, Siyu Wang, Jie Liu, Zhiyuan Du, Chenchen Yin, Shasha Fan, Haodong Li, Hao Wang, Yanwei Zhang, Pengyao Su, Mengfan Zhang, Lina Xuan, Mingyu Zhang, Lihua Sun, Lei Jiao, Yanyan Dong, Xu Wang, Manyu Gong, Baofeng Yang, Ying Zhang","doi":"10.1093/jmcb/mjag005","DOIUrl":"https://doi.org/10.1093/jmcb/mjag005","url":null,"abstract":"<p><p>Cardiac aging is associated with progressive cardiac fibrosis and dysfunction, yet the underlying mechanisms remain incompletely understood. Extrachromosomal circular DNA (eccDNA) has been reported to participate in tumor and age-related genomic instability, while its role in cardiac fibrosis during aging remains to be fully elucidated. In this study, circular DNA sequencing and RNA seqencing were performed to analyze eccDNA profiles in young and aged cardiac tissues. The number of eccDNAs in the cardiac tissue of aged mice is higher than that in young mice. Combining the annotation of eccDNAs and the key genes related to aging identified in the transcriptome, we identified sterile alpha and TIR motif containing 1 (Sarm1), a key regulator of NAD+ metabolism and neurodegeneration located in eccDNAs, as a novel driver of cardiac aging via pro-fibrotic signaling. In aged mice, Sarm1 knockdown significantly restored cardiac function and reduced fibrosis. Conversely, Sarm1 accelerated cardiac aging phenotypes in young Sarm1-overexpressing transgenic mice. Mechanistically, co-immunoprecipitation combined with mass spectrometry identified TGF-β-Smad2/3 as the dominant pathway, with pharmacological inhibition by SIS3 abolishing Sarm1-driven Smad2/3 phosphorylation. Our findings reveal that Sarm1-containing eccDNA drives cardiac aging by amplifying pro-fibrotic signaling through the TGF-β-Smad2/3 pathway, proposing eccDNAs clearance and Sarm1 inhibition as novel therapeutic strategies for aging-related cardiac fibrosis.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147326464","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}

{"title":"Association between targeted inflammatory proteomics and insulin sensitivity as well as beta-cell function in subjects with normal glucose tolerance.","authors":"Anran Chen, Qian Li, Hongfeng Mao, Yuwei Lu, Dan Liu, Lei Zhang, Qichen Fang, Chen Wang, Huating Li, Weiping Jia","doi":"10.1093/jmcb/mjaf035","DOIUrl":"10.1093/jmcb/mjaf035","url":null,"abstract":"<p><p>Obese individuals even with normal glucose tolerance (NGT) are at higher risk for developing type 2 diabetes (T2D), and obesity is associated with inflammation. However, mechanisms linking inflammation to beta-cell function and insulin sensitivity in NGT individuals are not fully understood. We aimed to investigate the relationships between inflammation-related proteins (IRPs) and insulin dynamics in NGT subjects. The explorations were conducted using data from 1109 non-diabetes subjects aged 40-44 with normal or excess body weight and 21 Chinese NGT subjects aged 22-32 with accurate metabolic assessment. IRPs were detected with Olink technology. Insulin sensitivity and beta-cell function were evaluated with hyperinsulinemic-euglycemic clamp and hyperglycemic clamp. Eight associators were identified with obesity in NGT subjects, among which MCP-3, IL-6, TWEAK, HGF, and CST5 also showed associations in non-diabetes people. Four IRPs were linked to insulin sensitivity, with IL-24 being a novel finding. Seven IRPs were related to beta-cell function, including novel associators CD244, CD40, and IL-15RA. Moreover, most IRPs were interconnected, with IL-6 as the hub. In conclusion, insulin sensitivity and beta-cell function are related to IRPs involved in chemotaxis, activation of immune cells, and cell proliferation, which might provide valuable information for the understanding of the mechanisms associated with T2D pathogenesis.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12976601/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145445016","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}

{"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":"10.1093/jmcb/mjaf031","url":null,"abstract":"<p><p>Tyrosine kinase inhibitor (TKI) 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. We employed an automatic liver tumor segmentation system, based on a two-stage 3D U-Net framework, to delineate 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. Next, we developed a clinical model using only pretreatment clinical information, a CNN model using only pretreatment magnetic resonance imaging data, and an advanced multimodal CNN-Transformer model fusing both imaging and clinical parameters from a training cohort (n = 181) and then compared their predictive performances in 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-nucleus 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.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12901565/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"African swine fever virus DEAD-box helicase D1133L promotes OGG1-driven incision of genomic 8-oxoG via HDAC5 deacetylation.","authors":"Jie Fan, Jifei Yang, Zhancheng Tian, Xiaoqiang Zhang, Shuxian Geng, Jianxun Luo, Istvan Boldogh, Qiaoying Zeng, Hong Yin, Guiquan Guan, Qingli Niu","doi":"10.1093/jmcb/mjaf029","DOIUrl":"10.1093/jmcb/mjaf029","url":null,"abstract":"<p><p>African swine fever virus (ASFV) infection induces oxidative stress and produces oxidative DNA damage bases, leading to oxidative DNA base damage, including the formation of 8-oxoguanine (8-oxoG). Prompt repair of these lesions is essential to maintain genome stability. The enzyme 8-oxoguanine DNA glycosylase 1 (OGG1) initiates the base excision repair (BER) pathway by recognizing and incising 8-oxoG, while also regulating multiple biological processes through interactions with host and viral proteins. In this study, we identified a specific interaction between the N-terminal region of ASFV DEAD-box helicase D1133L and OGG1, establishing a unique role for ASFV D1133L in DNA BER. Furthermore, we demonstrated for the first time that ASFV D1133L is a substrate for the histone acetyltransferases CBP/p300 in the nucleus. Conversely, deacetylation of D1133L by HDAC5, which predominantly occurs in the cytoplasm through its interaction with OGG1, markedly enhances OGG1 incision activity on 8-oxoG. Taken together, our findings reveal a previously unrecognized function of ASFV D1133L in promoting 8-oxoG repair by binding to OGG1 to safeguard genome integrity.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12902152/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957518","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}

{"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":"10.1093/jmcb/mjaf034","url":null,"abstract":"<p><p>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 utilization as it significantly increases the risk of primary graft dysfunction and acute rejection following transplantation. This risk is particularly high for organs obtained from donation after circulatory death (DCD) when compared with the organs from donation after 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 minimize tissue damage and improve clinical outcomes in organ transplantation. This review mainly discusses different types of regulated cell death and underlying mechanisms towards preventive cell death strategies in DBD and DCD organ transplantation in preclinical settings.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12907733/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comments on 'Macrophages form dendrite-like pseudopods to enhance bacterial ingestion'.","authors":"Changyuan Fan, Yaming Jiu","doi":"10.1093/jmcb/mjaf020","DOIUrl":"10.1093/jmcb/mjaf020","url":null,"abstract":"","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12901691/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144753625","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}

{"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":"10.1093/jmcb/mjaf030","url":null,"abstract":"<p><p>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 upon 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.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":6.0,"publicationDate":"2026-02-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12929916/pdf/","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":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"egr1 and egr4 regulate zebrafish renal regeneration by promoting foxm1 expression.","authors":"Xian He, Yuhua Sun","doi":"10.1093/jmcb/mjaf026","DOIUrl":"10.1093/jmcb/mjaf026","url":null,"abstract":"<p><p>Early growth response (Egr) factors are involved in tissue development and repair. However, few studies have focused on the role of egr genes in renal regeneration after acute kidney injury (AKI) and the underlying mechanisms. In this study, we observed that egr1 and egr4 were sharply upregulated in wild type zebrafish at 1 day post-injury by gentamicin. Further experiments with egr1 and egr4 mutants showed that egr1 and egr4 were involved in zebrafish renal regeneration after AKI by regulating the proliferation and apoptosis of tubular cells. foxm1 is expressed in injured kidneys and involved in kidney repair. Loss of foxm1 inhibited zebrafish renal regeneration by decreasing the proliferation and increasing the apoptosis of tubular cells. Moreover, Egr1 and Egr4 promoted foxm1 expression by directly binding to the foxm1 promoter, thus regulating renal regeneration. Our results revealed that the rapid and transient induction of egr1 and egr4 after AKI exerts a renoprotective role through upregulating foxm1 to facilitate kidney regeneration. Therefore, the egr1/egr4-foxm1 regulatory axis holds a therapeutic potential for the treatment of AKI.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12859677/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144855574","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}

{"title":"Targeting the ubiquitin-proteasome system and drug therapy in colorectal cancer.","authors":"Ruixin Su, Yingying Shao, Qian Wang, Donghui Liu, Yitong Wang, Dexin Kong, Yuling Qiu","doi":"10.1093/jmcb/mjaf027","DOIUrl":"10.1093/jmcb/mjaf027","url":null,"abstract":"<p><p>Colorectal cancer (CRC) is the third most prevalent malignancy worldwide and the second leading cause of cancer-associated deaths, posing a significant threat to human health. Given the limited therapeutic options and poor prognosis associated with CRC, there is an urgent need to develop new targeted therapeutic strategies to enhance clinical outcomes. The ubiquitin-proteasome system (UPS), a central regulator for cellular protein homeostasis, plays a pivotal role in the initiation and progression of CRC. The UPS modulates several essential signaling pathways and is involved in regulating tumor immunity and resistance to chemotherapy. Thus, the UPS contributes significantly to the complex biological processes underlying CRC pathogenesis. In recent years, small-molecule compounds targeting the UPS have exhibited considerable therapeutic potential in CRC treatment. These drugs intervene in crucial steps in the UPS, such as the activity of E1, E2, and E3 enzymes, or directly target the proteasome, thereby regulating the degradation of oncogenic proteins and effectively impeding tumor progression. Moreover, emerging therapeutic strategies such as proteolysis-targeting chimera (PROTAC) and molecular glue technologies selectively degrade specific oncogenic proteins, thereby offering new avenues and promising opportunities for CRC treatment.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12839529/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144957491","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}

{"title":"RNA-binding protein Rbm38 as a multifaceted post-transcriptional regulator in zebrafish pancreatic development.","authors":"Xiangmin Zhang, Xianpeng Li, Rui Liu, Lu Wang, Yunchao Wang, Ailong Zhang, Shuaiqi Yang, Hongyan Li","doi":"10.1093/jmcb/mjaf025","DOIUrl":"10.1093/jmcb/mjaf025","url":null,"abstract":"<p><p>RNA-binding motif protein 38 (Rbm38), also known as RNPC1, is a major regulator of post-transcriptional gene expression. It represents a potential candidate gene linked to the susceptibility of type 2 diabetes, and decreased RBM38 expression can enhance the proliferation of pancreatic cancer cells in humans. However, its role in pancreatic development remains elusive. In this study, we explored the function of Rbm38 using zebrafish as a model. Pancreatic expression of Rbm38 is present at larval stages and is controlled by several transcription factors acting on specific rbm38 promoter regions. The loss of Rbm38 leads to abnormal pancreatic enlargement. Mechanistically, Rbm38 is involved in several aspects of post-transcriptional regulation of pancreatic gene expression. It destabilizes pdx1 transcripts by binding to the 3'-untranslated region and regulates alternative splicing of key pancreatic transcription factor genes, including isl1a, smad2, and nkx2.2a. These findings elucidate the role of Rbm38 in pancreatic development and highlight its significance in maintaining pancreatic homeostasis.</p>","PeriodicalId":16433,"journal":{"name":"Journal of Molecular Cell Biology","volume":" ","pages":""},"PeriodicalIF":5.9,"publicationDate":"2026-01-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12866639/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144835370","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}