Cellular and Molecular Life Sciences最新文献

{"title":"Correction: USP1 inhibits influenza A and B virus replication in MDCK cells by mediating RIG-I deubiquitination.","authors":"Yuejiao Liao, Siya Wang, Tian Tang, Chengfang Li, Chenhao Yang, Liyuan Ma, Jin Ye, Jiamin Wang, Di Yang, Zilin Qiao, Zhongren Ma, Zhenbin Liu","doi":"10.1007/s00018-025-05794-7","DOIUrl":"10.1007/s00018-025-05794-7","url":null,"abstract":"","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"278"},"PeriodicalIF":6.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667303","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":"Macrophage migration inhibitory factor mediates joint capsule fibrosis via facilitating phospholipid metabolite PGE2 production in fibroblasts.","authors":"Yuxin Zhang, Xin Jiao, Yijia Wang, Shilu Liu, Zengguang Wang, Hanwen Chang, Yuntao Li, Xiaokun Yue, Xiaoding Gu, Renjie Xu","doi":"10.1007/s00018-025-05800-y","DOIUrl":"10.1007/s00018-025-05800-y","url":null,"abstract":"<p><strong>Background: </strong>Joint capsule persistent inflammation and subsequent fibrosis lead to post-traumatic joint contracture (PTJC). Fibroblasts, as a bridge between inflammation and fibrosis, participate in regulating the pathological microenvironment after injury. Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that can be inducibly expressed in lesioned joint capsule, yet its role in regulating fibroblast function to tune milieu following PTJC remains elusive.</p><p><strong>Methods: </strong>The influence of MIF on the expression of phospholipid metabolite prostaglandin E2 (PGE2) and relevant pathways were investigated using qRT-PCR, Western blot, ELISA, EdU, Transwell, siRNA, and immunofluorescence following establishment of rat PTJC model, fibroblast model, and macrophage model.</p><p><strong>Results: </strong>MIF/COX2/PGE2 synchronously increased in injured joint capsules following PTJC. Treatment the lesion sites with MIF inhibitor 4-IPP significantly reduced the expression of COX2 and PGE2. In vitro, MIF activated COX2/PGE2 pathway in joint capsule fibroblasts through interaction with membrane receptor CD74 and subsequent regulation of ERK/CREB signaling. Joint capsule fibroblast-derived PGE2 in turn selectively modulated fibroblast and macrophage functions to synergistically promote the inflammation and fibrosis process.</p><p><strong>Conclusions: </strong>Our results reveal a novel function of MIF-mediated fibroblast, which tunes pathological microenvironment by activating phospholipid metabolism to accelerate and exacerbate joint capsule inflammation and fibrosis. These suggest a new insights and potential therapeutic strategy for inflammation- and fibrosis-associated diseases.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"279"},"PeriodicalIF":6.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276190/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667308","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":"CXCL12/CXCR4 modulates macrophage efferocytosis to induce glomerular crescent formation and fibrosis via ELMO1/DOCK180/RAC1 signaling in ANCA-associated glomerulonephritis.","authors":"Zilin Liu, Yongqi Deng, Xiaomei Song, Xin Cai, Huaying Xiong, Liwen Tan, Shengsen Wei, Qiulin Li, Xiong Wang, Wei Jiang, Yaxi Chen, Qiu Li, Mo Wang","doi":"10.1007/s00018-025-05750-5","DOIUrl":"10.1007/s00018-025-05750-5","url":null,"abstract":"<p><strong>Background: </strong>ANCA-associated glomerulonephritis (AAGN) is a leading cause of uremia in children, driven by macrophages (Mφs) that mediate crescent formation and fibrosis. Despite their critical role, the signals governing monocyte recruitment and macrophage polarization in AAGN remain unclear.</p><p><strong>Methods: </strong>We utilized single-cell sequencing to dissect the cellular dynamics of AAGN and conducted in vitro and in vivo experiments to explore the role of the CXCL12/CXCR4 signaling axis in monocyte recruitment and macrophage efferocytosis. Protein interaction analyses further delineated the downstream signaling pathways involved.</p><p><strong>Results: </strong>CXCL12, released by apoptotic glomerular endothelial cells, recruited CXCR4⁺ monocytes to renal tissue, where they differentiated into M2-polarized macrophages and contributed to the progression of AAGN. CXCR4 signaling mediated M2 polarization via the ELMO1/DOCK180/ RAC1 efferocytosis pathway, resulting in the secretion of TGF-β1 to promote the progression of the crescent to fibrosis. Plasma CXCL12 and CXCR4 levels, along with CXCR4⁺ macrophage infiltration, distinguished AAGN from other crescentic nephritis types. LIT927 and AMD3100 treatment significantly alleviated renal dysfunction and crescent formation in EAV models.</p><p><strong>Conclusions: </strong>This study revealed that CXCL12/CXCR4 signaling axis plays a key regulatory role in the pathological process of AAGN. By establishing the specific molecular dialogue mechanism between endothelial cells and monocytes/macrophages, CXCL12 released by apoptotic endothelial cells can activate the CXCR4 on the surface of monocytes/macrophages, thereby promoting monocyte migration, enhancing macrophage-mediated efferocytosis and transforming into a pro-fibrotic phenotype. Targeted intervention with CXCL12/CXCR4 provides a promising approach for the treatment of AAGN.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"280"},"PeriodicalIF":6.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276188/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667304","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":"Pleckstrin-2 promotes the progression of colorectal cancer via YTHDF2-mediated TYMS mRNA stability.","authors":"Qian Zhou, Yanxia Li, Xiaomei Li, Shujing Zhang, Ying Wang, Zhuoran Li, Xia Wang, Yuan Li, Jingxin Li, Chunhua Lu, Yuemao Shen, Baobing Zhao","doi":"10.1007/s00018-025-05782-x","DOIUrl":"10.1007/s00018-025-05782-x","url":null,"abstract":"<p><p>High expression of nucleotide synthetic enzyme thymidylate synthase (TYMS) is responsible for the resistance to fluorouracil (FU) treatment and worse survival in colorectal cancer (CRC). Herein, we revealed that pleckstrin-2 (PLEK2) cooperated with YTHDF2 to enhance TYMS mRNA stability in CRC via an m⁶A dependent manner. Silencing of PLEK2 led to the degradation of TYMS mRNA that suppressed DNA replication, which activated p53/p21 signaling and consequent inhibition of CRC cell proliferation via the cellular senescence. Additionally, PLEK2 is also required for CRC cell migration, invasion and stemness-like properties. PLEK2 inhibition is sufficient to ameliorate the progression of AOM/DSS-induced CRC. Together, our study identified PLEK2 as a key regulator for the progress of CRC via the regulation of TYMS expression, and demonstrated that PLEK2 is a novel therapeutic target for CRC.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"284"},"PeriodicalIF":6.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276184/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667309","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":"Transcriptome remodelling and changes in growth and cardiometabolic phenotype result following Grb10a knockdown in the early life of the zebrafish.","authors":"Bridget L Evans, Terence Garner, Chiara De Leonibus, Lily Wright, Megan Sharps, Oliver H Wearing, Daniel M Ripley, Holly A Shiels, Adam F L Hurlstone, Peter E Clayton, Adam Stevens","doi":"10.1007/s00018-025-05784-9","DOIUrl":"10.1007/s00018-025-05784-9","url":null,"abstract":"<p><p>Embryonic growth trajectory is a risk factor for chronic metabolic and cardiovascular disorders. Grb10 is a negative regulator of the main pathways driving embryonic growth. This study has characterised growth, cardiometabolic status, and the impact on co-ordination of gene expression following morpholino-induced embryonic and early larval knockdown (KD) of grb10a expression in zebrafish (Danio rerio). Grb10 knockdown was associated with increased embryonic growth and metabolic rate, and decreased heart rate in early life. Juvenile growth rate was also elevated. The transcriptome was assessed over 5 to 30 days post fertilisation, coinciding with major changes in zebrafish (ZF) maturation and development. Significant and persistent organisational and functional changes in the whole transcriptome over this time were evident, including dysregulation of multiple growth, cardiac, and metabolic pathways. In adulthood (18 months), KD ZF had greater body length and mass than controls, with elevated cardiac muscle content, an increased aerobic scope, and higher fasting glucose levels. This study demonstrates that early life disruption of a single gene in zebrafish can result in long-term transcriptomic remodelling and alterations to the adult cardiometabolic phenotype.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"281"},"PeriodicalIF":6.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276197/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667310","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":"Ferroptosis and gut microbiota: A new horizon in alcohol-associated liver disease management.","authors":"Yue Chen, Wenkang Gao, Kailin Cai, Ling Yang, Huikuan Chu","doi":"10.1007/s00018-025-05815-5","DOIUrl":"10.1007/s00018-025-05815-5","url":null,"abstract":"<p><p>Alcohol-associated liver disease (ALD) is one of the most common chronic liver diseases worldwide, contributing significantly to liver cirrhosis and hepatocellular carcinoma, with limited effective treatment options. Approximately 50% of patients with ALD exhibit iron overload, which can further trigger the occurrence of ferroptosis. Recent studies indicate that ferroptosis plays a role in the development and progression of ALD through pro-inflammatory and pro-fibrotic mechanisms. Additionally, the gut microbiota exerts a complex influence on ALD, with pathogens like Candida albicans and Enterococcus faecalis promoting its progression, whereas Bifidobacterium appears to have a protective effect. Emerging findings indicate that microorganisms like Lactobacillus and metabolites such as 1,3-diaminopropane and reuterin can modulate iron homeostasis. However, the intrinsic link between gut microbiota-derived metabolites and ferroptosis in ALD remains inconclusive. This review comprehensively synthesizes current knowledge regarding the microbiota-ferroptosis crosstalk in ALD, with particular emphasis on microbial regulation of hepatic iron homeostasis and microbiota-driven modulation of oxidative stress through lipid peroxidation and antioxidant system interactions. Notably, we propose either suppressing hepatic ferroptosis or inducing ferroptosis in pathogenic bacterial strains as dual therapeutic strategies to mitigate ALD progression. These insights highlight the therapeutic potential of the gut microbiota-ferroptosis axis, paving the way for precision management strategies in ALD.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"282"},"PeriodicalIF":6.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276196/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667305","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":"From IP3RPEP6 Inhibition of IP₃ receptor channels to insights: do channel subunits collaborate or cooperate?","authors":"Katja Witschas, Siyu Tao, Luc Leybaert","doi":"10.1007/s00018-025-05813-7","DOIUrl":"10.1007/s00018-025-05813-7","url":null,"abstract":"<p><p>Inositol 1,4,5-trisphosphate (IP₃) receptor channels are intracellular ion channels activated by IP₃ and provoking Ca²⁺ release from ER/SR stores, playing fundamental roles in various cell functions ranging from fertilization up to cell death control. The channels are tetrameric structures centered around a Ca²⁺-permeable pore, which mutually interact to control channel opening initiated by both IP₃ and cytoplasmic Ca²⁺. IP₃ receptor (IP3R) channels come in 3 distinct subtypes with cryo-EM data currently being available for IP3R1 and IP3R3. These studies have demonstrated that IP₃ association with the IP₃ binding core (IBC) of a given subunit, triggers retraction of the ARM2 domain in a neighbor subunit, leading to IP₃ capture by the IBC of the initiating subunit, demonstrating subunit collaboration. ARM2 of IP3R2/3 contains a self-binding peptide that associates with the IBC but becomes displaced upon ARM2 retraction, thereby uncovering the IBC of a neighbor subunit, facilitating IP₃ access and thus potentially providing subunit cooperation. Distinct from collaboration, subunit cooperation has the potential to be forwarded across all 4 subunits. We here provide novel insight and understanding on the role of both IP₃ and Ca²⁺ in the steeply negative Hill behavior observed for IP3R inhibition by IP3RPEP6, a self-binding peptide derived from the ARM2 domain. In this light, we discuss the broad variety of reported IP3R Hill slopes and conclude that subunit cooperation operates at both activation and inhibition levels, suggesting adaptability to the cell state to either provide a well-titrated or an all-or-nothing response depending on the conditions and necessity.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"285"},"PeriodicalIF":6.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276195/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667306","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":"Ceramide and the membrane-fusion activity of LC3/GABARAP autophagy proteins.","authors":"Yaiza R Varela, Camila C Aguirre, Marina N Iriondo, Uxue Ballesteros, M Isabel Collado, Asier Etxaniz, L Ruth Montes, Felix M Goñi, Alicia Alonso","doi":"10.1007/s00018-025-05811-9","DOIUrl":"10.1007/s00018-025-05811-9","url":null,"abstract":"<p><p>Macroautophagy is a cellular degradation process characterized by the formation of the double-membrane structure termed autophagosome (AP). The process of AP formation is not fully understood, but it is thought to happen through the combined action of direct lipid transfer and incorporation of new vesicles to the edges of the growing structure. Human LC3/GABARAP autophagy-related proteins are known to induce vesicle tethering and lipid mixing in vitro, which makes them suitable for the latter expansion mechanism. Ceramide (Cer) is a sphingolipid previously described to facilitate membrane fusion. Cer has also been related to macroautophagy modulation previously, although its specific role remains unclear. Moreover, the presence of sphingolipids in the AP has been suggested by recent experiments, increasing the relevance of Cer in macroautophagy. The present work has investigated the potential role that Cer could have on the proposed fusion of new vesicles to the nascent AP membrane. Interaction of purified ATG proteins with lipid vesicles of defined composition has been quantified using fluorescence spectroscopic techniques. Our results suggest that, if present, Cer could promote the vesicle tethering and leakage-free intervesicular lipid mixing induced by GABARAP and GABARAPL1, which would in turn mediate AP membrane expansion.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"283"},"PeriodicalIF":6.2,"publicationDate":"2025-07-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12276180/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144667302","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":"Ferroptosis in cancer: revealing the multifaceted functions of mitochondria.","authors":"Xinyi Ding, Lei Cui, Yanjun Mi, Jiachun Hu, Zheyou Cai, Qing Tang, Linhao Yang, Zhuang Yang, Qingbing Wang, Hongsheng Li, Benxin Hou, Quentin Liu, Zhengzhi Zou, Yibing Chen","doi":"10.1007/s00018-025-05812-8","DOIUrl":"10.1007/s00018-025-05812-8","url":null,"abstract":"<p><p>Ferroptosis is a programmed cell death characterized by iron-dependent lipid peroxidation, which is regulated by various cellular metabolic and signaling pathways. The main regulatory mechanisms of intracellular ferroptosis include the GSH-GPX4 pathway, the FSP1-CoQ10 pathway, the GCH1-BH4 pathway, and the DHODH-CoQH2 system. As the hub of iron metabolism and energy generation, mitochondria have been increasingly implicated in ferroptosis, underscoring their pivotal role in cellular processes. Ferroptosis is a significant mode of cell demise linked to cancer progression. It is expected to combat drug-resistant tumors by triggering iron-mediated cell death. This review delves into the intricate mechanisms governing intracellular ferroptosis, emphasizing the centrality of mitochondria in regulating this process within cancer cells. Furthermore, this review explores the potential and hurdles of targeting ferroptosis as a therapeutic avenue to overcome resistance to cancer treatment.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"277"},"PeriodicalIF":6.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12271051/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658581","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":"LRRK2 kinase modulates glucose-stimulated insulin secretion via RAB8 phosphorylation and ciliogenesis.","authors":"Nevia Dule, Algerta Marku, Alessandra Galli, Francesca Pischedda, Adriano Lama, Michela Castagna, Paola Marciani, Federico Bertuzzi, Giovanni Piccoli, Carla Perego","doi":"10.1007/s00018-025-05810-w","DOIUrl":"10.1007/s00018-025-05810-w","url":null,"abstract":"<p><p>Leucine-rich repeat kinase 2 (LRRK2) encodes a multidomain protein whose mutations have been identified as genetic risk factors for Parkinson's disease (PD), an age-related neurodegenerative disorder. Outside the nervous system, LRRK2 is expressed in multiple tissues, including the endocrine pancreas, but its role here is unknown. Using pharmacological and molecular approaches, we show that LRRK2 kinase activity regulates stimulated insulin secretion by influencing secretory granule trafficking. The PD-associated LRRK2 mutant G2019S, characterized by enhanced kinase activity, increases the basal insulin release in complementary in vitro models and affects the metabolic profile in transgenic mice. Mechanistically, we demonstrate that LRRK2 kinase activity influences the formation of the primary cilium, an antenna-like structure acting as signaling platform to regulate hormones secretion. Specifically, LRRK2 phosphorylates RAB8 in a glucose-dependent manner, facilitating its recruitment to the primary cilium. These findings identify LRRK2 as a regulator of insulin secretion in pancreatic β-cells. Given the role of insulin signaling and glucose homeostasis in the nervous system, our data suggest that LRRK2 may also contribute to PD development through peripheral action.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"276"},"PeriodicalIF":6.2,"publicationDate":"2025-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12270992/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144658582","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}