Cellular and Molecular Life Sciences最新文献

{"title":"GADD45A suppression contributes to cardiac remodeling by promoting inflammation, fibrosis and hypertrophy.","authors":"Adel Rostami, Xavier Palomer, Javier Pizarro-Delgado, Lucía Peña, Mònica Zamora, Marta Montori-Grau, Emma Barroso, Brenda Valenzuela-Alcaraz, Fàtima Crispi, Jesús M Salvador, Raquel García, María A Hurlé, Francisco Nistal, Manuel Vázquez-Carrera","doi":"10.1007/s00018-025-05704-x","DOIUrl":"https://doi.org/10.1007/s00018-025-05704-x","url":null,"abstract":"<p><p>The growth arrest and DNA damage inducible 45A (GADD45A) is a multifaceted protein associated with stress signaling and cellular injury. Aside its well-established tumor suppressor activity, recent studies point to additional roles for GADD45A, including the regulation of catabolic and anabolic pathways, or the prevention of inflammation, fibrosis, and oxidative stress in some tissues and organs. However, little is known about its function in cardiac disease. In this study, we aimed to evaluate the role of GADD45A in the heart by using mice with constitutive and systemic deletion of Gadd45a, and cardiac cells of human origin. Gadd45a suppression in knockout mice triggered cardiac fibrosis, inflammation, and apoptosis, and these changes correlated with an hyperactivation of the pro-inflammatory and pro-fibrotic transcription factors activator protein-1 (AP-1), nuclear factor-κB (NF-κB), and signal transducer and activator of transcription 3 (STAT3). Deletion of Gadd45a also resulted in substantial cardiac hypertrophy, which negatively impacted cardiac morphology and function in knockout mice. Consistent with this, GADD45A overexpression in human AC16 cardiomyocytes partially prevented the inflammatory and fibrotic responses induced by tumor necrosis factor-α (TNF-α). Overall, data presented in this study highlight an important role for GADD45A in the heart, since it may prevent inflammation, fibrosis, and apoptosis, and, by this means, preserve cardiac function and performance. Since fibrosis and inflammation are crucial in the progression of cardiac hypertrophy and subsequent heart failure, these results suggest that promoting the activity of this protein might be a promising therapeutic strategy to slow down the progression of these deleterious diseases.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"189"},"PeriodicalIF":6.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040809/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143975794","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":"Degradation rather than disassembly of necrotic debris is essential to enhance recovery after acute liver injury.","authors":"Sara Schuermans, Jusal Quanico, Caine Kestens, Sofie Vandendriessche, Emily Slowikowski, Maria-Laura Crijns, Noëmie Pörtner, Nele Berghmans, Geert Baggerman, Matheus Silvério Mattos, Paul Proost, Pedro Elias Marques","doi":"10.1007/s00018-025-05720-x","DOIUrl":"https://doi.org/10.1007/s00018-025-05720-x","url":null,"abstract":"<p><p>Necrotic cell death causes loss of membrane integrity, release of intracellular contents and deposition of necrotic cell debris. Effective clearance of this debris is crucial for resolving inflammation and promoting tissue recovery. While leukocyte phagocytosis plays a major role, soluble factors in the bloodstream also contribute to debris removal. Our study examined whether enzymatic degradation or disassembly of necrotic debris enhances clearance and improves outcomes in a mouse model of drug-induced liver injury. Using intravital microscopy and on-tissue spatially-resolved microproteomics, we demonstrated that necrotic debris is more complex than anticipated, containing DNA, filamentous actin, histones, complement C3, fibrin(ogen) and plasmin(ogen), among many other components. DNase 1 treatment facilitated recovery significantly by enhancing the clearance of DNA from necrotic areas, reducing circulating nucleosomes and actin, and lowering the associated inflammatory response. However, its effect on actin and other damage-associated molecular patterns in necrotic regions was limited. Treatment with short synthetic peptides, specifically 20-amino acid-long positively charged poly L-lysine (PLK) and negatively charged poly L-glutamic acid (PLE), which displace histones from debris in vitro, did not inhibit liver injury or promote recovery. Moreover, activating plasmin to disrupt fibrin encapsulation via tissue plasminogen activator (tPa) led to increased circulating actin levels and worsening of injury parameters. These findings suggest that fibrin encapsulation is important for containing necrotic debris and that enzymatic degradation of necrotic debris is a more effective strategy to enhance tissue recovery than targeting debris disassembly.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"190"},"PeriodicalIF":6.2,"publicationDate":"2025-04-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12040799/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961471","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":"Muscle mTOR controls iron homeostasis and ferritinophagy via NRF2, HIFs and AKT/PKB signaling pathways.","authors":"Agnès Conjard-Duplany, Alexis Osseni, Aline Lamboux, Sandrine Mouradian, Flavien Picard, Vincent Moncollin, Céline Angleraux, Tiphaine Dorel-Dubois, Hélène Puccio, Pascal Leblanc, Bruno Galy, Vincent Balter, Laurent Schaeffer, Yann-Gaël Gangloff","doi":"10.1007/s00018-025-05695-9","DOIUrl":"https://doi.org/10.1007/s00018-025-05695-9","url":null,"abstract":"<p><p>Balanced mTOR activity and iron levels are crucial for muscle integrity, with evidence suggesting mTOR regulates cellular iron homeostasis. In this study, we investigated iron metabolism in muscle-specific mTOR knockout mice (mTORmKO) and its relation to their myopathy. The mTORmKO mice exhibited distinct iron content patterns across muscle types and ages. Slow-twitch soleus muscles initially showed reduced iron levels in young mice, which increased with the dystrophy progression but remained within control ranges. In contrast, the less affected fast-twitch muscles maintained near-normal iron levels from a young age. Interestingly, both mTORmKO muscle types exhibited iron metabolism markers indicative of iron excess, including decreased transferrin receptor 1 (TFR1) and increased levels of ferritin (FTL) and ferroportin (FPN) proteins. Paradoxically, these changes were accompanied by downregulated Ftl and Fpn mRNA levels, indicating post-transcriptional regulation. This discordant regulation resulted from disruption of key iron metabolism pathways, including NRF2/NFE2L2, HIFs, and AKT/PKB signaling. Mechanistically, mTOR deficiency impaired transcriptional regulation of iron-related genes mediated by NRF2 and HIFs. Furthermore, it triggered ferritin accumulation through two NRF2 mechanisms: (1) derepression of ferritin translation via suppression of the FBXL5-IRP axis, and (2) autophagosomal sequestration driven by NCOA4-dependent ferritin targeting to autophagosomes, coupled with age-related impairments of autophagy linked to chronic AKT/PKB activation. Three-week spermidine supplementation in older mTORmKO mice was associated with normalized AKT/PKB-FOXO signaling, increased endolysosomal FTL and reduced total FTL levels in the dystrophic soleus muscle. These findings underscore mTOR's crucial role in skeletal muscle iron metabolism and suggest spermidine as a potential strategy to address impaired ferritinophagy due to autophagy blockade in dystrophic muscle.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"178"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037468/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978212","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":"The potential of brain organoids in addressing the heterogeneity of synucleinopathies.","authors":"Xiao-Jun Diao, Claudio Soto, Fei Wang, Yu Wang, Yun-Cheng Wu, Abhisek Mukherjee","doi":"10.1007/s00018-025-05686-w","DOIUrl":"https://doi.org/10.1007/s00018-025-05686-w","url":null,"abstract":"<p><p>Synucleinopathies are a group of diseases characterized by neuronal and glial accumulation of α-synuclein (aSyn) linked with different clinical presentations, including Parkinson's disease (PD), Parkinson's disease with dementia (PDD), Dementia with Lewy Bodies (DLB) and Multiple system atrophy (MSA). Interestingly, the structure of the aSyn aggregates can vary across different synucleinopathies. Currently, it is unclear how the aSyn protein can aggregate into diverse structures and affect distinct cell types and various brain regions, leading to different clinical symptoms. Recent advances in induced pluripotent stem cells (iPSCs)-based brain organoids (BOs) technology provide an unprecedented opportunity to define the etiology of synucleinopathies in human brain cells within their three-dimensional (3D) context. In this review, we will summarize current advances in investigating the mechanisms of synucleinopathies using BOs and discuss the scope of this platform to define mechanisms underlining the selective vulnerability of cell types and brain regions in synucleinopathies.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"188"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978606","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":"The multifunctional regulatory post-proline protease dipeptidyl peptidase 9 and its inhibitors: new opportunities for therapeutics.","authors":"Jasmine Minh Hang Nguyen, Samuel Zolg, Ruth Geiss-Friedlander, Mark Douglas Gorrell","doi":"10.1007/s00018-025-05719-4","DOIUrl":"https://doi.org/10.1007/s00018-025-05719-4","url":null,"abstract":"<p><p>Dipeptidyl Peptidase 9 (DPP9) is a prolyl amino dipeptidylpeptidase that can cut a post-proline peptide bond at the penultimate position at the N-terminus. By removing N-terminal prolines, this intracellular peptidase acts as an upstream regulator of the N-degron pathway. DPP9 has crucial roles in inflammatory regulation, DNA repair, cellular homeostasis, and cellular proliferation, while its deregulation is linked to cancer and immunological disorders. Currently, there is no fully selective chemical inhibitor and the DPP9 knockout transgenic mouse model is conditional. Mice and humans in which DPP9 catalytic activity is absent die neonatally. DPP9 inhibition for manipulating DPP9 activity in vivo has potential uses and there is rapid progress towards DPP9 selectivity, with 170x selectivity achieved. This review discusses roles of DPP9 in biology and diseases and potential applications of compounds that inhibit DPP9 and its related proteases.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"187"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037458/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143978386","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":"Early involvement of D-serine in β-amyloid-dependent pathophysiology.","authors":"J-M Billard, E Ploux, S Largilliere, S Corvaisier, L Gorisse-Hussonnois, I Radzishevsky, H Wolosker, T Freret","doi":"10.1007/s00018-025-05691-z","DOIUrl":"https://doi.org/10.1007/s00018-025-05691-z","url":null,"abstract":"<p><p>The N-methyl-D-aspartate subtype of glutamate receptors (NMDAR) is a key regulator of brain plasticity encoding learning and memory. In addition to glutamate, NMDAR activation requires the binding of the co-agonist D-serine. The beta-amyloid (Aß) peptide which accumulates in Alzheimer's disease (AD), affects the D-serine-dependent NMDAR activation in vitro, but whether this alteration would significantly contribute to AD-related pathophysiology and memory deficits remains unclear. Herein, we report a decrease in the maximal pool of recruitable NMDAR and in the expression of NMDAR-dependent long-term potentiation together with impaired basal neurotransmission at CA3/CA1 synapses from hippocampal slices of 5xFAD mouse, an AD-related model with elevated Aß levels. The NMDAR synaptic impairments develop from 1.5 to 2 months of age with the initial rise of Aß and is correlated to a transient increase in D-serine levels. Deficits in working and spatial memories as well as cognitive flexibility then occurred in 10-12 months-old animals. Importantly, the NMDA-related synaptic deregulations (but not the altered basal neurotransmission) and behavioral impairments (working and cognitive flexibility) are prevented or reduced (spatial memory) in 5xFAD mice devoid of D-serine after genetic deletion of its synthesis enzyme serine racemase. Altogether, these results therefore provide in vivo evidence for the implication of D-serine at least in the early pathogenic signatures of AD driven by the increase in amyloid load suggesting that the recent proposal of preventive therapy of AD by administration of the precursor L-serine remains questionable.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"179"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037454/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961387","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":"m⁶A-modified MIR670HG suppresses tumor liver metastasis through enhancing Kupffer cell phagocytosis.","authors":"Wan-Peng Lu, Yong-da Liu, Zhi-Fa Zhang, Jia Liu, Jing-Wen Ye, Si-Yun Wang, Xing-Yi Lin, Yi-Ran Lai, Jie Li, Sui-Yi Liu, Ji-Hang Yuan, Xiao-Ting Zhu","doi":"10.1007/s00018-025-05700-1","DOIUrl":"https://doi.org/10.1007/s00018-025-05700-1","url":null,"abstract":"<p><p>Liver metastases are frequently observed in various malignancies, including hepatocellular carcinoma, colorectal cancer, pancreatic cancer, and melanoma. As hepatic resident macrophages, Kupffer cells play a crucial role in resisting liver metastasis by phagocytosing and clearing invading tumor cells. However, the molecular mechanisms regulating Kupffer cell phagocytosis and liver metastasis remain largely unknown. Here, we demonstrate that the MIR670 host gene (MIR670HG) significantly suppresses tumor liver metastasis by enhancing phagocytosis of various tumor cells by Kupffer cells. CD24 was identified as a downstream target and critical mediator of MIR670HG in promoting Kupffer cell phagocytosis and inhibiting tumor liver metastasis. Further investigations revealed that MIR670HG interacts with the m⁶A reader FXR1 and DNA 5-methylcytosine dioxygenase TET1 in an m⁶A modification-dependent manner. These interactions reduce the binding of TET1 to CD24 promoter, leading to increased DNA methylation at CD24 promoter and transcriptional suppression of CD24. Mutation of the m⁶A modification site abolishes the ability of MIR670HG to suppress CD24, promote Kupffer cell phagocytosis, and inhibit liver metastasis. In clinical tissue samples, MIR670HG expression negatively correlated with CD24 and liver metastasis. These findings suggest that m⁶A-modified MIR670HG promotes phagocytosis of tumor cells by Kupffer cells and suppresses liver metastasis by epigenetically downregulating CD24.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"185"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037464/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143992981","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":"Symbiotic bracovirus of a parasite modulate host ecdysis process.","authors":"Licheng Gu, Mujuan Guo, Pengzhan Wang, Jianchao Zhao, Zhiwei Wu, Zihan Wang, Sijie Zhang, Xin Yang, Ruofei Ma, Lizhi Wang, Xiqian Ye, Jianhua Huang, Xue-Xin Chen, Zhizhi Wang","doi":"10.1007/s00018-025-05717-6","DOIUrl":"https://doi.org/10.1007/s00018-025-05717-6","url":null,"abstract":"<p><p>Parasitoids modulate host development for the survival of their offspring, but the mechanisms underlying this phenomenon remain largely unknown. Here, we found that the endoparasitoid Cotesia vestalis disrupted the larval-larval ecdysis in its host Plutella xylostella by the 20-hydroxyecdysone (20E) synthesis pathway. After parasitization by C. vestalis, the 20E peak of host larvae disappeared before the onset of ecdysis and the expression of ecdysone synthesis genes was significantly downregulated. We further found that a Cotesia vestalis bracovirus (CvBV) gene CvBV_28 - 5 was transiently high-level expressed prior to the host's 20E peak, enabling the precise suppression of this critical developmental signal. Consistently, the knockdown of CvBV_28 - 5 affected the expression of 20E response transcription factors in the cuticle and several ecdysis-related genes. Furthermore, we found that CvBV_28 - 5 bound directly to the Raf, a MAP3K member of the MAPK pathwaythat functions as a critical regulator of ecdysone synthesis genes in hosts. Collectively, our results provide the first evidence that parasitoids modulate host ecdysis by affecting MAPK-20E signaling during a defined developmental window and provide novel insights into the mechanism of parasitoid regulation of host development.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"183"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037451/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143980442","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":"Dissecting inflammation in the immunemetabolomic era.","authors":"Patricia P Ogger, Peter J Murray","doi":"10.1007/s00018-025-05715-8","DOIUrl":"https://doi.org/10.1007/s00018-025-05715-8","url":null,"abstract":"<p><p>The role of immune metabolism, specific metabolites and cell-intrinsic and -extrinsic metabolic states across the time course of an inflammatory response are emerging knowledge. Targeted and untargeted metabolomic analysis is essential to understand how immune cells adapt their metabolic program throughout an immune response. In addition, metabolomic analysis can aid to identify pathophysiological patterns in inflammatory disease. Here, we discuss new metabolomic findings within the transition from inflammation to resolution, focusing on three key programs of immunity: Efferocytosis, IL-10 signaling and trained immunity. Particularly the tryptophan-derived metabolite kynurenine was identified as essential for efferocytosis and inflammation resolution as well as a potential biomarker in diverse inflammatory conditions. In summary, metabolomic analysis and integration with transcriptomic and proteomic data, high resolution imaging and spatial information is key to unravel metabolic drivers and dependencies during inflammation and progression to tissue-repair.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"182"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037969/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143961473","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":"Single-cell multi-dimensional data analysis decodes RNF19A-mediated drug resistance in rheumatoid arthritis fibroblast-like synoviocytes: mechanisms and biological insights.","authors":"Xin Luo, Ning Tang, Yijun Ren, Jingchen Li, Huancheng Zhu, Song Wu, Zhiyu Ding","doi":"10.1007/s00018-025-05707-8","DOIUrl":"https://doi.org/10.1007/s00018-025-05707-8","url":null,"abstract":"<p><p>Rheumatoid arthritis (RA) is a prevalent autoimmune disease, affecting approximately 1% of the global population. Methotrexate (MTX) is the most widely prescribed drug for RA treatment; however, its efficacy is often limited, with resistance frequently observed. Fibroblast-like synoviocytes (FLS) play a pivotal role in RA progression and are closely linked to drug resistance, although the underlying mechanisms remain poorly understood. In this study, we conducted a comprehensive analysis of public single-cell transcriptomics data from osteoarthritis and rheumatoid arthritis synovial tissues, identifying RNF19A as a gene potentially associated with RA resistance in FLS. Our findings indicate that RNF19A is significantly overexpressed in drug-resistant FLS and is closely associated with the dysregulation of FLS proliferation, migration, invasion, and apoptosis. Furthermore, we demonstrated that RNF19A promotes functional disruption in FLS by ubiquitinating and degrading MKP-1, thereby activating the MAPK signaling pathway. This activation also facilitates the nuclear translocation of ZBTB20, an upstream transcription factor of RNF19A, which further enhances RNF19A transcription. This biological process creates a positive feedback loop in FLS, contributing to RA resistance-a mechanism that was also validated in vivo. In summary, this study is the first to underscore the crucial role of RNF19A in mediating drug resistance in RA FLS, elucidating the underlying biological processes, and providing novel insights into RA pathogenesis, thereby offering a new experimental foundation for RA drug development.</p>","PeriodicalId":10007,"journal":{"name":"Cellular and Molecular Life Sciences","volume":"82 1","pages":"180"},"PeriodicalIF":6.2,"publicationDate":"2025-04-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12037462/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143954944","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}