Cell Death & Disease最新文献

{"title":"Usp11 maintained the survival of marginal zone B cells under ionizing radiation by deubiquitinating DLL1 and JAG2.","authors":"Jiaqi Sheng, Depei Wu, Jingzhe Shang, Xiaodan Fu, He Gao, Jianjie Rong, Jun Wang, Jiancheng Hu, Xiaofei Qi","doi":"10.1038/s41419-025-07377-7","DOIUrl":"10.1038/s41419-025-07377-7","url":null,"abstract":"<p><p>Efficacy of radiation therapy is compromised by hematopoietic and immune impairments, with elusive underlying causes. This study aimed to elucidate Usp11's role in radiation-induced injuries and uncover related mechanisms. Utilized ARS mouse model to observe survival rates of Usp11^-/- (KO) mice post-TBI (Total Body Irradiation). Assessed lymphocyte and MZ B (Marginal Zone B) cell rates using histological analysis, single-cell sequencing, immunofluorescence (IF), immunohistochemistry (IHC), and flow cytometry (FCM). Conducted Co-IP and ubiquitination experiments for mechanism elucidation. Quantified IgM and IgG using ELISA and FC. Explored public databases for potential correlation molecules. Our findings indicated that Usp11^-/- mice exhibited improved survival rates following TBI, with the spleen playing a pivotal role. HE staining revealed a wider marginal zone in the spleen of Usp11^+/+ mice post-irradiation. Single-cell sequencing, IF, IHC, and FCM analyses revealed a higher survival rate of MZ B cells in Usp11^-/- mice after irradiation. Furthermore, treatment with the Usp11 inhibitor, mitoxantrone, successfully targeted and inhibited Usp11, thereby alleviating the reduction in MZ B cells in the spleen following total body irradiation. Mechanistically, Usp11 sustained the survival of MZ B cells by regulating the ubiquitination of Notch's ligands, DLL1 and JAG2, thereby promoting immune cell remodeling in the spleen. In conclusion, Usp11 played a crucial role in modulating immune system damage induced by ionizing radiation, primarily through ubiquitination of Notch ligands. This study provides insights into radiation-induced immune injuries and suggests Usp11 as a potential therapeutic target.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"67"},"PeriodicalIF":8.1,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11794699/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143188459","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Irisin regulates oxidative stress and mitochondrial dysfunction through the UCP2-AMPK pathway in prion diseases.","authors":"Pei Wen, Zhixin Sun, Dongming Yang, Jie Li, Zhiping Li, Mengyang Zhao, DongDong Wang, Fengting Gou, Jingjing Wang, Yuexin Dai, Deming Zhao, Lifeng Yang","doi":"10.1038/s41419-025-07390-w","DOIUrl":"10.1038/s41419-025-07390-w","url":null,"abstract":"<p><p>Prion diseases are a group of fatal neurodegenerative disorders characterized by the abnormal folding of cellular prion proteins into pathogenic forms. The development of these diseases is intricately linked to oxidative stress and mitochondrial dysfunction. Irisin, an endogenous myokine, has demonstrated considerable neuroprotective potential due to its antioxidative properties. However, the protective effects of irisin against prion diseases have yet to be clarified. Our findings indicate that treatment with exogenous irisin can mitigate the apoptosis induced by PrP^106-126. Additionally, irisin significantly reduces oxidative stress and alleviates the mitochondrial dysfunction triggered by PrP^106-126. Furthermore, irisin treatment targets uncoupling protein 2 (UCP2) and activates the AMPK-Nrf2 pathway, substantially improving oxidative stress and mitochondrial dysfunction in N2a cells induced by PrP^106-126. These results suggest that irisin represents a novel and promising therapeutic approach for treating prion diseases.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"66"},"PeriodicalIF":8.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790890/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122328","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"LDHA-mediated glycolysis in stria vascularis endothelial cells regulates macrophages function through CX3CL1-CX3CR1 pathway in noise-induced oxidative stress.","authors":"Ying Yi, Min-Yu Wu, Kai-Tian Chen, An-Hai Chen, Lin-Qiu Li, Qin Xiong, Xian-Ren Wang, Wen-Bin Lei, Guan-Xia Xiong, Shu-Bin Fang","doi":"10.1038/s41419-025-07394-6","DOIUrl":"10.1038/s41419-025-07394-6","url":null,"abstract":"<p><p>According to the World Health Organization, more than 12% of the world's population suffers from noise-induced hearing loss (NIHL). Oxidative stress-mediated damage to the stria vascularis (SV) is one of the pathogenic mechanisms of NIHL. Recent studies indicate that glycolysis plays a critical role in endothelial cells (ECs)-related diseases. However, the specific role of glycolysis in dysfunction of SV-ECs remain largely unknown. In this study, we investigated the effects of glycolysis on SV-ECs in vitro and on the SV in vivo. Our previous research identified the glycolysis pathway as a potential mechanism underlying the SV-ECs injuries induced by oxidative stress. We further examined the expression levels of glycolytic genes in SV-ECs under H₂O₂ stimulation and in noise-exposed mice. We found that the gene and protein expression levels of glycolytic-related enzyme LDHA significantly decreased at early phase after oxidative stress injury both in vitro and in vivo, and exhibited anti-inflammatory effects on macrophages (Mφ). Moreover, we analyzed the differential secretomes of SV-ECs with and without inhibition of LDHA using LC-MS/MS technology, identifying CX3CL1 as a candidate mediator for cellular communication between SV-ECs and Mφ. We found that CX3CL1 secretion from SV-ECs was decreased following LDHA inhibition and exhibited anti-inflammatory effects on Mφ via the CX3CR1 pathway. Similarly, the pro-inflammatory effect of LDHA-overexpressing SV-ECs was attenuated following inhibition of CX3CL1. In conclusion, our study revealed that glycolysis-related LDHA was reduced in oxidative stress-induced SV-ECs, and that LDHA inhibition in SV-ECs elicited anti-inflammatory effects on Mφ, at least partially through the CX3CL1-CX3CR1 pathway. These findings suggest that LDHA represent a novel therapeutic strategy for the treatment of NIHL.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"65"},"PeriodicalIF":8.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122329","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Enhanced ferroptosis sensitivity promotes the formation of highly myopic cataract via the DDR2-Hippo pathway.","authors":"Dongling Guo, Yu Du, Xin Liu, Dan Li, Ling Wei, Xiangjia Zhu","doi":"10.1038/s41419-025-07384-8","DOIUrl":"10.1038/s41419-025-07384-8","url":null,"abstract":"<p><p>Highly myopic cataract (HMC) is a leading cause of blindness among the working-age individuals, with its pathogenesis poorly understood. This study aimed to elucidate the role of ferroptosis in HMC development as well as the underlying mechanisms. In HMC lens epithelia, levels of Fe²⁺ and lipid peroxidation were found elevated, with increased vulnerability towards ferroptosis as revealed by transmission electron microscopy. Mechanistically, RNA sequencing of HMC lens epithelial samples identified up-regulated expression of discoidin domain receptor tyrosine kinase 2 (DDR2) as a key factor, which could enhance ferroptosis sensitivity via the Src-Hippo pathway. Specifically, DDR2 interacted with Src kinase, leading to the nuclear translocation of homologous transcriptional regulators (yes-associated protein 1 [YAP1] and WW domain containing transcription regulator 1 [WWTR1]) of the Hippo pathway, which altered the expression level of ferroptosis-related genes. Notably, highly myopic eyes of mice exhibited higher sensitivity to RSL3, a ferroptosis inducer, manifested as more severe nuclear lens opacities both in vitro and in vivo compared with the contralateral control eyes, which could be alleviated by inhibitors of either ferroptosis or DDR2. Altogether, these findings highlighted the role of DDR2 in mediating ferroptosis in HMC formation, providing a novel insight for therapeutic interventions.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"64"},"PeriodicalIF":8.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11790942/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122326","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FAM210B activates STAT1/IRF9/IFIT3 axis by upregulating IFN-α/β expression to impede the progression of lung adenocarcinoma.","authors":"Xuejuan Gao, Donglan Huang, Ying Liu, Gui Zhang, Xiaofen Zheng, Baiye Guan, Aiwen Chen, Jiayao Wu, Shi-Ming Luo, Zonghua Liu, Luxuan Chen, Xiaohui Liu, Jingjie Jin, Xingfeng Yin, Zhenghua Sun, Yunfang Zhang, Meizhi Lu, Gong Zhang, Wanting Liu, Langxia Liu","doi":"10.1038/s41419-025-07375-9","DOIUrl":"10.1038/s41419-025-07375-9","url":null,"abstract":"<p><p>FAM210B (family with sequence similarity 210 member B) is a novel protein that has been linked to tumor development. However, its role and underlying mechanisms in lung adenocarcinoma (LUAD) progression remain largely unexplored. In this study, FAM210B was observed to be down-regulated in LUAD cells. Analyses of public datasets revealed that decreased expression of FAM210B predicts poor survival. Accordingly, in vitro and in vivo studies have confirmed the inhibitory role of FAM210B on the growth and tumor metastasis of LUAD cells. RNA-seq analysis further indicated that FAM210B plays a role in regulating innate immune-related signaling pathways in LUAD cells, particularly involving the production of type I interferon (IFN-α/β). Specifically, FAM210B activates STAT1/IRF9/IFIT3 axis by upregulating IFN-α/β expression, leading to the inhibition of proliferation and migration of LUAD cells. Furthermore, TOM70 (Translocase of outer mitochondrial membrane 70, also named as TOMM70) has been identified as a functional interacting partner of FAM210B in its modulation on the expression of IFN-α/β, as well as the proliferative and metastatic phenotypes of LUAD cells. In conclusion, our study indicates that FAM210B is an important suppressor of cellular viability and mobility during lung cancer progression.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"63"},"PeriodicalIF":8.1,"publicationDate":"2025-02-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11791038/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Long noncoding RNA GDIL acts as a scaffold for CHAC1 and XRN2 to promote platinum resistance of colorectal cancer through inhibition of glutathione degradation.","authors":"Xuan Deng, Lu Chang, Lingyu Tang, Haoqin Jiang, Xiao Xu, Xinju Zhang, Jian Chen, Liu Dong, Qianqian Xu, Ruoshui Cao, Jianbin Xiang, Ming Guan","doi":"10.1038/s41419-025-07374-w","DOIUrl":"10.1038/s41419-025-07374-w","url":null,"abstract":"<p><p>Acquired resistance poses a significant obstacle to the effectiveness of platinum-based treatment for cancers. As the most abundant antioxidant, glutathione (GSH) enables cancer cell survival and chemoresistance, by scavenging excessive reactive oxygen species (ROS) induced by platinum. Therapeutic strategy targeting GSH synthesis has been developed, however, failed to produce desirable effects in preventing cancer progression. Thus, uncovering mechanisms of rewired GSH metabolism may aid in the development of additional therapeutic strategies to overcome or delay resistance. Here, we identify upregulation of long noncoding RNA (lncRNA) GDIL (GSH Degradation Inhibiting LncRNA) in platinum resistant colorectal cancer (CRC) and ovarian cancer cells compared with parental ones. High expression of GDIL in resistant CRC is associated with poor survival and hyposensitivity to chemotherapy. We demonstrate that GDIL boosted GSH levels and enhances clearance of ROS induced by platinum. Metabolomic and metabolic flux analysis further reveals that GDIL promotes GSH accumulation by inhibiting GSH degradation. This is attributed by downregulation of CHAC1, an enzyme that specifically degrades intracellular GSH. Mechanistically, GDIL binds and re-localizes the nuclear protein XRN2 to the cytoplasm, where GDIL further serve as a scaffold for XRN2 to identify and degrade CHAC1 mRNA. Suppression of GDIL with selective antisense oligonucleotide, restored drug sensitivity in platinum resistant cell lines and delayed drug resistance in cell line- and patient-derived xenografts. Thus, lncRNA GDIL is a novel target to promote GSH degradation and augment platinum therapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"62"},"PeriodicalIF":8.1,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11787370/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074011","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRIM21-mediated PRMT1 degradation attenuates colorectal cancer malignant progression.","authors":"Menghan Cao, Zhiying Shao, Xingyou Qian, Miaolei Chen, Chuyin Deng, Xintian Chen, Tingting Tang, Kaixu Zhang, Sufang Chu, Junnian Zheng, Jin Bai, Zhongwei Li","doi":"10.1038/s41419-025-07383-9","DOIUrl":"10.1038/s41419-025-07383-9","url":null,"abstract":"<p><p>Tripartite motif-containing 21 (TRIM21) plays a crucial role in antiviral responses and autoimmune diseases. While the impact of TRIM21 on cancer has been studied in various tumors, its role in colorectal cancer (CRC) remains unclear. In this study, we found that TRIM21 expression is reduced in primary CRC tissues. Low levels of TRIM21 in CRC are associated with unfavorable clinicopathological characteristics and shorter survival. Furthermore, we demonstrate that TRIM21 suppresses the proliferation, tumorigenesis, migration, and metastasis of CRC cells by promoting the ubiquitination-mediated degradation of PRMT1. These findings suggest that TRIM21 holds potential as a valuable predictive biomarker for assessing the prognosis of CRC patients.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"56"},"PeriodicalIF":8.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785787/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074020","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human proximal tubular epithelial cell interleukin-1 receptor signalling triggers G2/M arrest and cellular senescence during hypoxic kidney injury.","authors":"Kurt T K Giuliani, Purba Nag, Benjamin C Adams, Xiangju Wang, Seokchan Hong, Anca Grivei, Rebecca L Johnston, Nicola Waddell, Kenneth K C Ho, Yilin Tian, Muhammad Ali Khan, Chang Seong Kim, Monica S Y Ng, Glenda Gobe, Jacobus P J Ungerer, Josephine M Forbes, Helen G Healy, Andrew J Kassianos","doi":"10.1038/s41419-025-07386-6","DOIUrl":"10.1038/s41419-025-07386-6","url":null,"abstract":"<p><p>Hypoxia and interleukin (IL)-1β are independent mediators of tubulointerstitial fibrosis, the histological hallmark of chronic kidney disease (CKD). Here, we examine how hypoxia and IL-1β act in synergy to augment maladaptive proximal tubular epithelial cell (PTEC) repair in human CKD. Ex vivo patient-derived PTECs were cultured under normoxic (21% O₂) or hypoxic (1% O₂) conditions in the absence or presence of IL-1β and examined for maladaptive repair signatures. Hypoxic PTECs incubated with IL-1β displayed a discrete transcriptomic profile distinct from PTECs cultured under hypoxia alone, IL-1β alone or under normoxia. Hypoxia+IL-1β-treated PTECs had 692 'unique' differentially expressed genes (DEGs) compared to normoxic PTECs, with 'cell cycle' the most significantly enriched KEGG pathway based on 'unique' down-regulated DEGs (including CCNA2, CCNB1 and CCNB2). Hypoxia+IL-1β-treated PTECs displayed signatures of cellular senescence, with reduced proliferation, G2/M cell cycle arrest, increased p21 expression, elevated senescence-associated β-galactosidase (SA-β-gal) activity and increased production of pro-inflammatory/fibrotic senescence-associated secretory phenotype (SASP) factors compared to normoxic conditions. Treatment of Hypoxia+IL-1β-treated PTECs with either a type I IL-1 receptor (IL-1RI) neutralizing antibody or a senolytic drug combination, quercetin+dasatinib, attenuated senescent cell burden. In vitro findings were validated in human CKD bio-specimens (kidney tissue, urine), with elevated PTEC IL-1RI expression and senescence (SA-β-gal activity) detected in fibrotic kidneys and numbers of senescent (SA-β-gal⁺) urinary PTECs correlating with urinary IL-1β levels and severity of interstitial fibrosis. Our data identify a mechanism whereby hypoxia in combination with IL-1β/IL-1RI signalling trigger PTEC senescence, providing novel therapeutic and diagnostic check-points for restoring tubular regeneration in human CKD.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"61"},"PeriodicalIF":8.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074008","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Estrogen-dependent activation of TRX2 reverses oxidative stress and metabolic dysfunction associated with steatotic disease.","authors":"Alfredo Smiriglia, Nicla Lorito, Marina Bacci, Angela Subbiani, Francesca Bonechi, Giuseppina Comito, Marta Anna Kowalik, Andrea Perra, Andrea Morandi","doi":"10.1038/s41419-025-07331-7","DOIUrl":"10.1038/s41419-025-07331-7","url":null,"abstract":"<p><p>Metabolic dysfunction-associated steatotic liver disease (MASLD) encompasses a spectrum of hepatic disorders, ranging from simple steatosis to steatohepatitis, with the most severe outcomes including cirrhosis, liver failure, and hepatocellular carcinoma. Notably, MASLD prevalence is lower in premenopausal women than in men, suggesting a potential protective role of estrogens in mitigating disease onset and progression. In this study, we utilized preclinical in vitro models-immortalized cell lines and hepatocyte-like cells derived from human embryonic stem cells-exposed to clinically relevant steatotic-inducing agents. These exposures led to lipid droplet (LD) accumulation, increased reactive oxygen species (ROS) levels, and mitochondrial dysfunction, along with decreased expression of markers associated with hepatocyte functionality and differentiation. Estrogen treatment in steatotic-induced liver cells resulted in reduced ROS levels and LD content while preserving mitochondrial integrity, mediated by the upregulation of mitochondrial thioredoxin 2 (TRX2), an antioxidant system regulated by the estrogen receptor. Furthermore, disruption of TRX2, either pharmacologically using auranofin or through genetic interference, was sufficient to counteract the protective effects of estrogens, highlighting a potential mechanism through which estrogens may prevent or slow MASLD progression.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"57"},"PeriodicalIF":8.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785963/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074002","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smad4 deficiency in hepatocytes attenuates NAFLD progression via inhibition of lipogenesis and macrophage polarization.","authors":"Wei Yang, Xuanxuan Yan, Rui Chen, Xin Xin, Shuang Ge, Yongxiang Zhao, Xinlong Yan, Jinhua Zhang","doi":"10.1038/s41419-025-07376-8","DOIUrl":"10.1038/s41419-025-07376-8","url":null,"abstract":"<p><p>Nonalcoholic fatty liver disease (NAFLD), a major cause of chronic liver disorders, has become a serious public health issue. Although the Smad4 signaling pathway has been implicated in the progression of NAFLD, the specific role of Smad4 in hepatocytes in NAFLD pathogenesis remains unclear. Hepatocyte-specific knockout Smad4 mice (Alb^Smad4-/-) were first constructed using the Cre-Loxp recombinant system to establish a high-fat diet induced NAFLD model. The role of Smad4 in the occurrence and development of NAFLD was determined by monitoring the body weight of mice, detecting triglycerides and free fatty acids in serum and liver tissue homogenates, staining the tissue sections to observe the accumulation of liver fat, and RT-qPCR detecting the expression of genes related to lipogenesis, fatty acid intake, and fatty acid β oxidation. The molecular mechanism of Smad4 in hepatocytes affecting NAFLD was therefore investigated through combining in vitro and in vivo experiments. Smad4 deficiency in hepatocytes mitigated NAFLD progression and decreased inflammatory cell infiltration. Moreover, Smad4 deficiency inhibited CXCL1 secretion by suppressing the activation of the ASK1/P38/JNK signaling pathway. Furthermore, targeting CXCL1 using CXCR2 inhibitors diminished hepatocyte lipogenesis and inhibited the polarization of M1-type macrophages. Collectively, these results suggested that Smad4 plays a vital role in exacerbating NAFLD and may be a promising candidate for anti-NAFLD therapy.</p>","PeriodicalId":9734,"journal":{"name":"Cell Death & Disease","volume":"16 1","pages":"58"},"PeriodicalIF":8.1,"publicationDate":"2025-01-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11785999/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143074017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}