Experimental cell research最新文献

{"title":"Promoter architecture and enhancer-driven regulation of Cdh1 during MET","authors":"Neslihan Toyran ,&nbsp;Hani Alotaibi","doi":"10.1016/j.yexcr.2025.114748","DOIUrl":"10.1016/j.yexcr.2025.114748","url":null,"abstract":"<div><div>E-cadherin (Cdh1) reactivation is a hallmark of the mesenchymal-to-epithelial transition (MET); however, the direct regulatory mechanisms controlling Cdh1 promoter activity remain incompletely understood. Here, we systematically analyzed the responsiveness of the Cdh1 promoter to MET-associated transcription factors using luciferase reporter assays and chromatin immunoprecipitation. An extended Cdh1 promoter fragment exhibited strong basal activity but limited modulation during EMT or MET. Promoter truncation modestly increased basal activity but was insufficient for robust activation. In contrast, integrating a Grhl3-responsive enhancer dramatically enhanced promoter responsiveness, enabling activation by Grhl3 and cooperative enhancement with Hnf4α. Chromatin immunoprecipitation confirmed Grhl3 enrichment at the Cdh1 promoter region during MET, consistent with the enhanced promoter responsiveness observed upon enhancer integration. These findings demonstrate that the dynamic regulation of Cdh1 expression during epithelial plasticity requires coordinated enhancer-promoter interactions and transcription factor recruitment to overcome intrinsic promoter constraints.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114748"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145046526","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"JPH203 alleviates renal fibrosis via inhibition of serine-related mTORC1 pathway in TGF-β1-induced fibroblasts and UUO mice","authors":"Changwan Cui ,&nbsp;Mengqi Hong ,&nbsp;Hainan Zhao ,&nbsp;Lei Wang ,&nbsp;Ying Yang ,&nbsp;Jingyu Wang ,&nbsp;Li Sun","doi":"10.1016/j.yexcr.2025.114732","DOIUrl":"10.1016/j.yexcr.2025.114732","url":null,"abstract":"<div><div>Renal fibrosis is the common pathological outcome of chronic kidney disease (CKD) progressing into end-stage renal disease. The excessive proliferation of fibroblasts plays an important role in the CKD progression. Nutrients such as amino acids and their transportation are essential for cell proliferation. In this study, TGF-β1-induced fibroblasts and UUO mouse models were used. The target gene solute carrier family 7 member 5 (SLC7A5) was screened to be highly expressed and localized in the renal fibroblasts of CKD mice. In vivo experiments showed that SLC7A5 promoted the activation of mammalian target of rapamycin complex 1 (mTORC1) signaling pathway, enhanced serine synthesis and maintained oxidative stress balance in fibroblasts. SLC7A5 increased the expression of transcription factor activating transcription factor 4 (ATF4), promoted the transcription of serine de-novo synthesis enzyme PHGDH, and increased the synthesis of glutathione, a byproduct of serine synthesis pathway. JPH203, a specific inhibitor of SLC7A5, effectively reversed the above phenomena, inhibited mTORC1 signaling activation, and reduced the proliferation of fibroblasts. The efficacy of JPH203 was further verified by in vivo experiments. JPH203 had a similar effect to the inhibitory adenovirus AV-shSLC7A5 in the UUO mouse model. Compared with the UUO group, the activation of mTORC1 pathway in the JPH203 treatment group was inhibited, and the expressions of α-SMA and vimentin in fibroblasts were decreased. The fibrotic state of renal tissues was effectively relieved. In addition, the levels of serum creatinine, blood urea nitrogen and pelvic urinary protein were significantly decreased compared with the UUO group. In conclusion, our study demonstrated that JPH203 can alleviate renal fibrosis via inhibition of serine-related mTORC1 pathway in fibroblasts in UUO mice. These results may provide a theoretical foundation for the pathogenesis of renal fibrosis and a novel therapeutic strategy for CKD.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114732"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014159","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"HMGB1 contributes to pancreatic fibrosis by regulating TLR4-mediated autophagy and the NLRP3 inflammasome pathway in chronic pancreatitis","authors":"Caixia Li ,&nbsp;Lihua Cui ,&nbsp;Yanjie Zuo ,&nbsp;Jianhong Pan ,&nbsp;Xiao Li ,&nbsp;Xinsheng Xu ,&nbsp;Lanqiu Zhang ,&nbsp;Yuzhen Zhuo ,&nbsp;Guowang Yao ,&nbsp;Zhenyu Wang ,&nbsp;Shukun Zhang","doi":"10.1016/j.yexcr.2025.114745","DOIUrl":"10.1016/j.yexcr.2025.114745","url":null,"abstract":"<div><div>The characteristic pathological change in chronic pancreatitis (CP) is pancreatic fibrosis. In the early stages of CP development, injured acinar cells induce the infiltration of inflammatory cells, followed by pancreatic stellate cell (PSC) activation. Activated PSC induce the deposition of extracellular matrix (ECM) and promote the development of pancreatic fibrosis. High-mobility group Box 1 (HMGB1) is a damage-associated molecular pattern (DAMP) molecule. Although HMGB1 is implicated in several types of fibrotic diseases, its functional role and mechanism in pancreatic fibrosis in CP remain unknown. In this study, a dibutyltin dichloride (DBTC)-induced rat CP model was constructed in vivo. The results revealed that HMGB1 translocates from the nucleus of acinar cells to the cytoplasm and is subsequently released into the extracellular space, thereby promoting the progression of pancreatic fibrosis in CP. PSC was isolated and exposed to varying concentrations of HMGB1 in vitro. Resatorvid and <em>si-TLR4</em> were applied to verify that the functions of HMGB1 were realized by combining with TLR4. 3-MA, <em>si</em>-<em>Atg5</em> and MCC950 were used to determine the effect of HMGB1 on PSC activation through the regulation of autophagy and the NLRP3 inflammasome. These results indicated that exogenous administration of HMGB1 induces PSC activation and ECM deposition through its receptor TLR4. Mechanistically, the HMGB1/TLR4 axis promoted PSC activation by promoting autophagy–NLRP3 inflammasome activation. Our study highlights the profibrotic role of HMGB1 and provides a novel therapeutic target for the treatment of CP.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114745"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014192","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"SIRT1 rescues autophagic flux via PI3K/AKT/mTOR inactivation to suppress DOX-induced senescence in MCF-7 cells","authors":"Ge Wu ,&nbsp;Wei Yao ,&nbsp;Lin Cheng ,&nbsp;Xiaoping Wang ,&nbsp;Tongsheng Chen","doi":"10.1016/j.yexcr.2025.114754","DOIUrl":"10.1016/j.yexcr.2025.114754","url":null,"abstract":"<div><div>Sirtuin 1 (SIRT1), a deacetylase, has been extensively studied for its roles in regulating autophagy, aging, cellular metabolism and tumorigenesis. In this study, we investigated how SIRT1 modulates doxorubicin (DOX)-induced senescence in MCF-7 cells, a breast cancer cell line. SIRT1 significantly reduced the DOX-induced elevation of senescence-associated proteins p53, p21, and SA-β-Gal activity, revealing that SIRT1 inhibited DOX-induced senescence. Notably, SIRT1 increased the DOX-induced upregulation of p62 accumulation and reversed the DOX-induced decrease in the LC3II/LC3I ratio, revealing that SIRT1 reversed the DOX-induced blockage of autophagic flux. The autophagy inhibitor chloroquine (CQ) partially abolished the anti-aging effects of SIRT1, indicating that autophagy mediated the anti-aging effects of SIRT1. Additionally, SIRT1 suppressed the DOX-induced activation of the phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway, thereby facilitating autophagy. The PI3K inhibitor LY294002 enhanced the anti-aging effect of SIRT1 which, however, was reversed by the AKT activator SC-79. In conclusion, our study reveals that SIRT1 counteracts DOX-induced senescence in MCF-7 cells by inactivating PI3K/AKT/mTOR pathway.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114754"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145080151","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A floating endometrial organoid model recapitulates epithelial-stromal cell interactions in vitro","authors":"Adriana Bajetto ,&nbsp;Alessandra Pattarozzi ,&nbsp;Alessandro Corsaro ,&nbsp;Beatrice Tremonti ,&nbsp;Monica Gatti ,&nbsp;Valerio Pisaturo ,&nbsp;Luisa Campagnolo ,&nbsp;Denise Colia ,&nbsp;Elena Pastine ,&nbsp;Alessandra Alteri ,&nbsp;Mauro Costa ,&nbsp;Stefano Thellung ,&nbsp;Federica Barbieri ,&nbsp;Tullio Florio","doi":"10.1016/j.yexcr.2025.114749","DOIUrl":"10.1016/j.yexcr.2025.114749","url":null,"abstract":"<div><div>Organoids are 3D structures in which stem, progenitor and differentiated cells spontaneously assemble into structures resembling the original tissue. Endometrial organoids, developed from tissue fragments, are genetically stable and responsive to hormone stimulation acquiring a hallow lumen, secretory activity and apico-basal polarity. However, they show some limitations in mimicking the midluteal endometrium since they lack endothelial, immune, and stromal cells, thus providing limited information about epithelial-stromal interactions. We developed a 3D-model to generate endometrial organoids in floating Matrigel™ droplets using standard medium. Floating organoids form gland-like structures constituted by epithelial cells organized around a central lumen, and contain stromal cells grown in close contact, either outside or inside the organoid structure. Similarly to conventional endometrial organoids, floating organoids retain the expression of endometrial and decidual genes, assessed by qRT-PCR for a panel of fifteen genes, although with a pattern of expression resembling, in most cases, what observed in hormonally differentiated organoids. In conclusion, we describe a simple and rapid model to generate 3D endometrial organoids, ensuring the persistence of epithelial-stromal cell interaction, which fosters the development of differentiated organoids, thereby enabling the study of the reciprocal modulation between epithelium and stroma.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114749"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145032868","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect and mechanism of CXCL9 overexpressed umbilical cord mesenchymal stem cells on liver fibrosis in vivo and in vitro","authors":"Yang Li ,&nbsp;Xueqian Zhang ,&nbsp;Guiyu Liu ,&nbsp;Tianci Tang ,&nbsp;Xueshuai Ye ,&nbsp;Jianhui Cai","doi":"10.1016/j.yexcr.2025.114750","DOIUrl":"10.1016/j.yexcr.2025.114750","url":null,"abstract":"<div><h3>Background</h3><div>Umbilical cord mesenchymal stem cells (UC-MSCs) transplantation has emerged as a promising therapeutic approach of liver fibrosis. However, UC-MSCs have limited anti-fibrotic ability for various reasons. In this study, we aimed to investigate whether the overexpression of CXCL9 in UC-MSCs (CXCL9-UC-MSC) could have synergistic anti-fibrotic effects and explore the possible mechanism.</div></div><div><h3>Methods</h3><div>We established the rat models of liver fibrosis and administered CXCL9-UC-MSC cells via tail vein injection for therapy. We assessed the improvement in liver lesion and liver function across different treatment groups, while further investigating the expression of various proteins within the TGF-β1/Smad3 signaling pathway. Additionally, we monitored the expression levels of α-SMA, Collagen-III and Collagen-I. In vitro studies were conducted using activated LX-2 cells to validate the cellular pathways and assess inhibition of activation.</div></div><div><h3>Results</h3><div>After cell therapy, pathological staining and liver function indicated that the area of liver fibrosis in the rats was reduced, the hepatocellular necrosis was alleviated, and liver function damage was improved. Notably, these improvements were more significant in the CXCL9-UC-MSC group. Furthermore, the expression levels of α-SMA, Collagen-III, Collagen-I, TGF-β1 and pSmad3 in the liver and LX-2 cells were significantly decreased after the CXCL9 intervention. Additionally, the abilities of proliferation, viability and invasiveness of LX-2 cells were also significantly inhibited with the intervention of CXCL9.</div></div><div><h3>Conclusion</h3><div>The overexpression of CXCL9 in UC-MSCs inhibited the activation of the TGF-β1/Smad3 signaling pathway, and reduced the expressions of α-SMA, Collagen-III and Collagen-I in liver and LX-2 cells, thereby exerting a more significant anti-fibrotic effect.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114750"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145039509","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"N4BP3 promotes ovarian cancer progression and paclitaxel resistance by activating the Wnt/β-catenin signaling through interaction with XPO1","authors":"Mingliang Fan ,&nbsp;Ke Liu ,&nbsp;Yonggang Shi ,&nbsp;Jie Hao ,&nbsp;Haifeng Qiu ,&nbsp;Yan Liang","doi":"10.1016/j.yexcr.2025.114751","DOIUrl":"10.1016/j.yexcr.2025.114751","url":null,"abstract":"<div><div>Ovarian cancer is a highly lethal gynecological malignancy worldwide, primarily attributed to late diagnosis and chemoresistance. The Nedd4-binding protein 3 (N4BP3) has been identified to function in the development of several cancers. However, its role in ovarian cancer remains unclear. The expression profile of N4BP3 and its association with patients' prognosis in ovarian cancer was analyzed through bioinformatic analysis. N4BP3 expression was confirmed in ovarian cancer cell lines. Subsequently, N4BP3 expression was manipulated to investigate its effects on the malignant phenotypes of ovarian cancer cells. Furthermore, paclitaxel (PTX)-resistant cell lines were established to examine N4BP3's influence on PTX resistance. The effects of N4BP3 on tumor growth and PTX resistance were further analyzed <em>in vivo</em>. The potential mechanisms of N4BP3 were explored using bioinformatic analysis, co-immunoprecipitation, and Western blot. We found that N4BP3 was highly expressed in ovarian cancer tissues, and patients with higher N4BP3 expression exhibited shorter overall survival and progression-free survival. N4BP3 expression was higher in ovarian cancer cell lines, with even higher levels in PTX-resistant cells. Upregulation of N4BP3 significantly promoted the proliferation and invasion, and elevated PTX resistance in ovarian cancer cells, while its downregulation had the opposite effects. Silencing of N4BP3 inhibited tumor growth and decreased PTX resistance in a xenograft mouse model. Mechanistically, N4BP3 activated the Wnt/β-catenin signaling through binding to XPO1. Taken together, N4BP3 promotes ovarian cancer progression and PTX resistance by activating the Wnt/β-catenin signaling through interaction with XPO1. N4BP3 may serve as a potential therapeutic target for the treatment of ovarian cancer.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114751"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145069396","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CircTTC3 regulates the osteogenic differentiation of adipose-derived mesenchymal stem cells via miR-205/Smad3 axis","authors":"Qiuling Zhang ,&nbsp;Zeyou Guo ,&nbsp;Wenzhong Hu,&nbsp;Weibing Tang,&nbsp;Xinzhe Gao,&nbsp;Cong Han,&nbsp;Xinyu Wang,&nbsp;Pei Gong,&nbsp;Jie Long","doi":"10.1016/j.yexcr.2025.114746","DOIUrl":"10.1016/j.yexcr.2025.114746","url":null,"abstract":"<div><div>Adipose-derived mesenchymal stem cells (ADSCs) hold great promise for bone tissue repair and regeneration. Circular RNAs (circRNAs) play a crucial role in regulating the osteogenic differentiation and bone remodeling of ADSCs; however, the underlying molecular mechanisms remain unclear. In this study, we conducted whole transcriptome sequencing (WTS) on ADSCs and constructed a competing endogenous RNA (ceRNA) regulatory network to identify the circTTC3/miR-205/mothers against decapentaplegic homolog 3 (Smad3) signaling axis. Subsequently, we used Sanger sequencing and agarose gel electrophoresis to verify the cyclization of circTTC3. We confirmed that circTTC3 promotes the osteogenic differentiation of ADSCs and demonstrated that circTTC3 co-localizes with miR-205 in the cytoplasm. Additionally, we showed that circTTC3 sponges miR-205 using dual-luciferase reporter assays and fluorescent in situ hybridization (FISH) experiments. Moreover, miR-205 targets the 3′ untranslated region (UTR) of Smad3. Rescue experiments further verified that circTTC3 mediates the osteogenic differentiation of ADSCs through the miR-205/Smad3 pathway. Finally, in vivo, animal studies revealed that circTTC3 overexpression enhances cranial defect repair while silencing circTTC3 disrupts new bone formation.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114746"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145014195","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hyperglycemia promotes tumor immune evasion via B7-H4 upregulation in ovarian cancer","authors":"Jing Yang,&nbsp;Jingjing Zhang,&nbsp;Zhenyan Wang,&nbsp;Lei Fu,&nbsp;Ming Liu,&nbsp;Zhaoyuan Niu","doi":"10.1016/j.yexcr.2025.114752","DOIUrl":"10.1016/j.yexcr.2025.114752","url":null,"abstract":"<div><h3>Background</h3><div>The efficacy of ICB therapy has long been shown to be less prominent in patients with metabolic disorders, including type II diabetes, but the underlying mechanisms remain unclear.</div></div><div><h3>Objective</h3><div>To investigate how hyperglycemia influences tumor immune evasion and suppresses CD8⁺ T cell function in ovarian cancer, focusing on the role of B7-H4 and AP-1.</div></div><div><h3>Methods</h3><div>The BKS db/db mice, a model of type II diabetes, and ID8 ovarian cancer cells were used to evaluate tumor growth, immune cell infiltration, and the impact of hyperglycemia on immune checkpoint expression. Flow cytometry, Western blotting, and chromatin immunoprecipitation (ChIP) assays were performed to explore the molecular mechanisms linking hyperglycemia to B7-H4 upregulation.</div></div><div><h3>Results</h3><div>Accelerated tumor growth and reduced responsiveness to ICB therapy were observed in BKS db/db mice in comparison to wild-type controls. Tumors from hyperglycemic mice exhibited significantly higher expression of B7-H4 due to reduced CD8⁺ T cell infiltration, diminished IFNγ production, and decreased activation markers (CD137 and CD107a). In vitro, high-glucose conditions resulted in increased B7-H4 expression in ovarian cancer cells via the AP-1 transcription factor. Furthermore, the knockdown of AP-1 led to a reduction in B7-H4 expression, a restoration of CD8⁺ T cell infiltration, and an enhancement of immune activation in hyperglycemic mice.</div></div><div><h3>Conclusion</h3><div>This study reveals that hyperglycemia promotes tumor immune evasion through AP-1-mediated B7-H4 upregulation in ovarian cancer cells, resulting in impaired CD8⁺ T cell function and reduced ICB efficacy. Targeting the AP-1/B7-H4 axis could provide a therapeutic strategy to improve immunotherapy outcomes in patients with metabolic disorders.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114752"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058468","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PERK suppression induces susceptibility to ferroptosis in lupus nephritis","authors":"Jin-Wen Xu ,&nbsp;Yan Wei ,&nbsp;Ming-Yan Wang ,&nbsp;Ling-Yun Yang ,&nbsp;Guo-Min Li","doi":"10.1016/j.yexcr.2025.114725","DOIUrl":"10.1016/j.yexcr.2025.114725","url":null,"abstract":"<div><div>Systemic Lupus Erythematosus (SLE) is an autoimmune disease, and the most common and serious complications in children is lupus nephritis (LN). Recent studies have identified ferroptosis as a pathological process present in both LN patients and mouse models of LN. However, the specific molecular mechanisms regulating ferroptosis in LN remain largely unexplored. Protein kinase RNA-like endoplasmic reticulum kinase (PERK) is a transmembrane protein involved in maintaining cellular homeostasis and promoting cell survival, has not been fully characterized in the context of LN. Our experimental findings have demonstrated that ferroptosis markers are significantly upregulated in LN patients and lupus mouse models. These changes include increased Fe²⁺ levels, decreased glutathione (GSH) content, and elevated mRNA expression of ferroptosis-associated genes. Interestingly, PERK and Solute Carrier Family 7 Member 11(SLC7A11, xCT) mRNA levels were markedly reduced in both LN patients and lupus mice compared to controls. Moreover, PERK expression showed a positive correlation with GSH levels, suggesting a potential protective role. Functional studies further revealed that PERK inhibition exacerbates renal injury and ferroptosis while reducing GSH content. In vitro experiments using HK-2 cells demonstrated that the ferroptosis inhibitor Fer-1 could restore GSH levels and counteract ferroptosis under PERK knockdown conditions. Mechanistically, PERK positively regulates the transcription of SLC7A11 via ATF4, highlighting its role in maintaining cellular redox balance. In conclusion, low PERK expression aggravate lupus nephritis by inhibiting SLC7A11 transcription via ATF4 and reducing GSH synthesis. These findings provide new directions and potential therapeutic targets for the role of PERK in the pathogenesis of LN.</div></div>","PeriodicalId":12227,"journal":{"name":"Experimental cell research","volume":"452 1","pages":"Article 114725"},"PeriodicalIF":3.5,"publicationDate":"2025-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144933929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}