The FASEB Journal最新文献

{"title":"ANXA4 Alleviates Cardiomyocyte Injury Associated With Ischemia–Reperfusion by Interfering With NFκB p50's Transcriptional Activation of RAGE","authors":"Zhihan Zhao,&nbsp;Yonghui Zhao,&nbsp;Xiaobiao Zang,&nbsp;Yuexia Ren,&nbsp;Weifeng Song,&nbsp;Lei Wang,&nbsp;Ke Chen,&nbsp;Erpeng Liang,&nbsp;You Zhou,&nbsp;Xianqing Wang,&nbsp;Kerun Niu","doi":"10.1096/fj.202501598R","DOIUrl":"10.1096/fj.202501598R","url":null,"abstract":"<div>\u0000 \u0000 <p>Myocardial ischemia/reperfusion injury (MI/R) remains a major challenge in cardiac transplantation, leading to early graft dysfunction or primary nonfunction, and eventually death. This study explores the role of annexin A4 (ANXA4), a calcium-dependent phospholipid-binding protein, in MI/R pathogenesis and investigates its underlying mechanisms. In C57BL/6J mice, ANXA4 expression was moderately increased following MI/R (induced by 45-min occlusion/24 h reperfusion) (mRNA: sham vs. MI/<i>R</i> = 1.00 vs. 2.42, <i>p</i> &lt; 0.01; protein: 1.00 vs. 2.39, <i>p</i> &lt; 0.05). To assess its functional role, AAV9 particles (1 × 10¹¹ viral genomes per mouse) carrying ANXA4 encoding fragments were intravenously injected into mice 4 weeks before the surgery. The forced elevation of ANXA4 reduced IR-induced myocardial infarction from 41.22% to 18.23%, lowered the ventricular arrhythmias score from 10.83 to 6.00, and creatinine kinase-myocardial band (CK-MB) activity from 450 to 268 U/L. ANXA4 overexpression also inhibited cardiomyocyte apoptosis, inflammation, and oxidative stress. In vitro, ANXA4 overexpression mediated by pcDNA3.1 vector protected HL-1 mouse cardiomyocytes against oxygen–glucose deprivation/reoxygenation (OGD/R)-induced cell damage. Further high-throughput transcriptomics illustrated that ANXA4 upregulation significantly suppressed the expression of the receptor for advanced glycosylation end products (RAGE; Log2 Fold change = −3.19, <i>p</i> &lt; 0.05). Mechanistically, ANXA4 repressed the transcription of RAGE by dampening the nuclear translocation of NFκB p50. Collectively, this study demonstrates that ANXA4 is upregulated in the mouse myocardium post MI/R as a compensatory response, and its overexpression alleviates MI/R- and OGD/R-induced cardiomyocyte injury by preventing NFκB p50 from binding to and initiating transcription of RAGE.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145082272","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Spatial Metabolism of Primary Limited Cutaneous Amyloidosis Based on Mass Spectrometry Imaging","authors":"Xinyue Liu,&nbsp;Zhijun Deng,&nbsp;Ziyi Wan,&nbsp;Kaixi Pan,&nbsp;Ping Lu","doi":"10.1096/fj.202402636RR","DOIUrl":"10.1096/fj.202402636RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Primary limited cutaneous amyloidosis (PLCA) is characterized by the amyloid deposition in the skin without systemic involvement. However, the precise composition and mechanisms underlying amyloid formation remain incompletely understood. In this study, skin tissues of PLCA and healthy controls (HC) were stained with Congo red and subsequently segmented based on staining patterns. Mass spectrometry imaging (MSI) was employed to analyze the spatial distribution of metabolites across these defined regions. By integrating variable importance in projection (VIP) values, folding changes (FC), and the biological functions of metabolites, several metabolites potentially linked to amyloid deposition in PLCA were identified from a pool of 1941 detected metabolites. Notably, elevated levels of arginine and its derivatives, lipoic acid, dihydrolipoic acid, and pyruvate were found in PLCA. KEGG pathway analysis revealed significant enrichment of the arginine biosynthesis pathway. Furthermore, immunohistochemical and RNA sequencing analyses demonstrated upregulated expression of arginase 1 (ARG1), an enzyme involved in arginine catabolism, in PLCA lesions. Subsequent in vitro studies indicated that arginine promoted the proliferation of HaCaT cells and upregulated keratin 5 (K5) expression, potentially implicating these processes in PLCA pathogenesis. Based on these findings, we propose that metabolic dysregulation—particularly in arginine metabolism—may play an important role in the pathogenesis of PLCA, providing new insights into the molecular mechanisms underlying this condition.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"NONO Maintains SREBP-Regulated Cholesterol Biosynthesis via RNA Binding in Neuroblastoma","authors":"Song Zhang,&nbsp;Hayley Ingram,&nbsp;Jack Cooper,&nbsp;Alina Naveed,&nbsp;Stefan G. Kathman,&nbsp;Garrett L. Lindsey,&nbsp;Tao Liu,&nbsp;Charles S. Bond,&nbsp;Jamie I. Fletcher,&nbsp;Benjamin F. Cravatt,&nbsp;Archa H. Fox","doi":"10.1096/fj.202403267RR","DOIUrl":"10.1096/fj.202403267RR","url":null,"abstract":"<p>High-risk neuroblastoma is associated with upregulation of cholesterol biosynthesis through increased expression of sterol regulatory element—binding protein (SREBP). NONO, a multifunctional nuclear RNA binding protein, is an established oncogene in neuroblastoma and can stabilize SREBP in breast cancer. Hence, here we addressed the unexplored question of NONO regulation of SREBP in neuroblastoma. We show NONO knockdown reduces cholesterol in neuroblastoma patient-derived tumor cell lines and high-risk neuroblastoma KELLY cells. NONO knockdown also reduces mRNA and protein expression of SREBP family members in KELLY cells. RNA-seq of NONO knockdown confirmed cholesterol synthesis pathway genes are downregulated. Further, only overexpression of NONO wild-type, rather than NONO mutant lacking the RNA recognition motif 1, could elevate SREBP levels after endogenous NONO knockdown, revealing the importance of NONO RNA binding activity. Finally, (R)-SKBG-1, a small molecule that modulates the RNA binding activity of NONO, hence altering its subnuclear distribution, significantly decreased cholesterol levels and SREBP target gene expression in KELLY cells. These results lend weight to manipulating NONO RNA binding as a potential therapeutic avenue for treating aggressive neuroblastoma.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439068/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070847","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 Role of Centrosome Misorientation and miR-1270 in Impaired Endothelial Cell Migration in Preeclampsia","authors":"Bianca Schröder-Heurich,&nbsp;Nadia Meyer,&nbsp;Katja Richter,&nbsp;Constantin S. von Kaisenberg,&nbsp;Frauke von Versen-Höynck","doi":"10.1096/fj.202502468R","DOIUrl":"10.1096/fj.202502468R","url":null,"abstract":"<p>Preeclampsia is a serious pregnancy-related disorder that poses significant health risks to the mother and offspring. A key aspect of preeclampsia is impaired endothelial cell migration, which is essential for the repair and integrity of the vasculature. Preeclamptic endothelial progenitor cells (EPC) exhibit defects in migration, although the precise molecular mechanisms underlying these defects remain unclear. Cellular spatial organization, such as centrosome orientation, regulates the migration process by influencing cell polarity and movement. Epigenetic changes in preeclampsia may disrupt these processes and thus impair endothelial function. We recently described the role of microRNA (miR)-1270 in preeclamptic EPC, linking its dysregulated expression to impaired EPC motility. Here, we demonstrate that endothelial cell migration defects in preeclampsia, along with reduced miR-1270 levels, are accompanied by changes in centrosome orientation. This study provides novel insights into the molecular consequences of preeclampsia and its detrimental effects on endothelial dynamics.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12439232/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145070844","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":"IGF2BP1/ORC1 Axis Influences Nonsmall Cell Lung Cancer Progression via m6A Methylation Modification","authors":"Kui Liu,&nbsp;Xiaoyan Yang,&nbsp;Xuemei Tang,&nbsp;Xionghuai Wang,&nbsp;Bo Tang","doi":"10.1096/fj.202501075RR","DOIUrl":"10.1096/fj.202501075RR","url":null,"abstract":"<div>\u0000 \u0000 <p>ORC1 is a gene involved in DNA replication and is linked to various diseases. However, the role of ORC1 in cancer remains incompletely understood. The relationship between ORC1-regulated epigenetic modifications and lung cancer progression has not been systematically analyzed. Bioinformatics analysis was utilized to assess differential ORC1 expression in NSCLC and normal tissues, as well as potential m6A methylation modifiers and m6A modification sites on ORC1. Clinical samples and cell experiments validated ORC1 expression in NSCLC. RNA pulldown, MeRIP-qPCR, and mRNA stability assays analyzed the regulatory relationship between ORC1 and IGF2BP1. Cell proliferation was measured using CCK-8, while flow cytometry assessed the cell cycle and apoptosis. Western blotting evaluated the expressions of proteins related to the cell cycle, proliferation, and apoptosis. The xenograft mouse model was built by injecting human NSCLC cells, and tumor growth was monitored. After humane euthanasia, tumors were collected for weighing and staining analysis. ORC1 was upregulated in NSCLC tissues and cells, and its silencing hindered NSCLC cell proliferation. IGF2BP1 enhanced ORC1 mRNA stability through m6A modification. Both in vitro and in vivo experiments demonstrated that IGF2BP1 overexpression fostered tumor proliferation and antiapoptotic capacity, while ORC1 silencing reversed these effects, highlighting the role of the IGF2BP1/ORC1 axis in NSCLC progression. IGF2BP1 enhanced ORC1 expression by modulating its m6A methylation modification, significantly influencing NSCLC progression. This study underscored the importance of the IGF2BP1/ORC1 axis in cancer progression.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062763","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TRPV2 Regulates Function of Human Neutrophil Granulocytes","authors":"Anna S. Heinemann,&nbsp;Tabea C. Fricke,&nbsp;Christine Herzog,&nbsp;Frank G. Echtermeyer,&nbsp;Andreas Leffler","doi":"10.1096/fj.202501585RR","DOIUrl":"10.1096/fj.202501585RR","url":null,"abstract":"<p>Neutrophils play a vital role in human immune defense, and their dysregulation can cause collateral damage in sepsis and autoimmune diseases. We provide evidence for the involvement of the transient receptor potential vanilloid 2 (TRPV2) in cytokine expression and transmigration in human neutrophils as well as in HL60 cells. These data identify TRPV2 as a candidate target for novel therapeutics regulating neutrophil activity.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501585RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062764","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":"Arachidonic Acid Protects Skeletal Muscle Against Hyperglycaemia-Induced Muscle Atrophy by Modulating Myogenesis and Regulating KLF15 Expression in C57Bl/6 Mice","authors":"Akash Mitra,&nbsp;Debajit Chaudhury,&nbsp;Akhila Balakrishna Rai,&nbsp;Undurti N. Das,&nbsp;Thottethodi Subrahmanya Keshava Prasad,&nbsp;Bipasha Bose,&nbsp;Sudheer Shenoy P","doi":"10.1096/fj.202502321RR","DOIUrl":"10.1096/fj.202502321RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Glucotoxicity or hyperglycemia as a consequence of Type 1 diabetes affects numerous tissues, including skeletal muscles, and translates to muscle wasting or atrophy. Since 40% of the total body weight comprises skeletal muscles, and because this tissue plays an essential role in voluntary movement, protecting its integrity is crucial for maintaining whole-body homeostasis. Although different studies have investigated the role of arachidonic acid (AA) in salvaging skeletal muscle atrophy, the underlying mechanisms concerning the activation of muscle stem cells and the regenerative process need further elucidation. In this study, we use a streptozotocin-induced Type 1 diabetes mouse model to study the effects of AA in mitigating the reduction in the myogenesis process and also try to elaborate on the anti-atrophic and anti-inflammatory properties of AA, which help to rescue the levels of sarcomeric protein. To carry out this study, male C57BL/6 mice (5-week-old) were divided into Control, diabetic (STZ) and AA-administered diabetic (STZ + AA) groups (<i>n</i> = 6 mice per group). The study involved a short-term treatment regime of 5 days. Muscle stem cell activation, inflammation, and muscle fiber integrity were assessed using molecular techniques. A global proteomic study provided insights into differential protein expression status. Histological analysis revealed the rescue of muscle cells at different stages of myogenesis and fiber integrity upon AA administration in diabetic mice. Moreover, the proteomic results supported the upregulation of stemness upon AA treatment as well. Additionally, it also showed the rescue of the sarcomeric protein repertoire. The findings suggest that AA holds myogenic properties, which stem from its role in activating the muscle stem cells, and this can be used as a potential therapeutic supplement for diabetic patients.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145062762","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Baicalin Alleviates Chronic Pancreatitis Fibrosis and Islet Dysfunction via Targeting IFNAR-Mediated JAK/STAT Signaling and Immune Modulation","authors":"Hehe Dou,&nbsp;Rui Tao,&nbsp;Kan Yue,&nbsp;Feng Cheng,&nbsp;Zhipeng Xu,&nbsp;Zhenjie Wang,&nbsp;Chuanming Zheng","doi":"10.1096/fj.202501649R","DOIUrl":"10.1096/fj.202501649R","url":null,"abstract":"<div>\u0000 \u0000 <p>Chronic pancreatitis (CP) is characterized by progressive fibrosis and islet dysfunction, yet effective therapeutic strategies remain limited. This study elucidates the mechanism by which baicalin ameliorates CP progression through modulation of the interferon-α/β receptor (IFNAR)/janus kinase (JAK)/signal transducer and activator of transcription (STAT) signaling pathway. In a caerulein-induced CP rat model, baicalin treatment (100 mg/kg/day, 6 weeks) markedly reduced pancreatic injury, collagen deposition, and α-smooth muscle actin (α-SMA) expression, alongside decreased serum levels of IL-6, TNF-α, TGF-β, amylase, and lipase. Flow cytometry revealed that baicalin suppressed pancreatic infiltration of CD8⁺ T cells, macrophages, and NK cells while elevating regulatory T (Treg) cell proportions. Transcriptomic analysis identified JAK/STAT signaling as a key pathway inhibited by baicalin, with molecular docking confirming its direct binding to IFNAR. In vitro, baicalin (10 μM) attenuated TGF-β1-activated pancreatic stellate cell (PSC) activation, evidenced by reduced lipid droplet loss and α-SMA/COL1A1 expression. Overexpression of IFNAR reversed baicalin's anti-fibrotic effects, whereas co-treatment with the JAK inhibitor ruxolitinib partially restored its efficacy. In vivo, IFNAR overexpression diminished baicalin's therapeutic benefits, but ruxolitinib co-administration mitigated pancreatic damage. These findings demonstrate that baicalin alleviates CP fibrosis and islet dysfunction by targeting IFNAR to suppress JAK/STAT signaling, modulating immune cell dynamics, and inhibiting PSC activation. This study highlights IFNAR as a novel therapeutic target and positions baicalin as a promising candidate for CP treatment.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058055","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Improvement of Spontaneous Locomotor Activity in a Murine Model of Duchenne Muscular Dystrophy by N-Acetylglucosamine Alone and in Combination With Prednisolone","authors":"Masahiko. S. Satoh,&nbsp;Guillaume St-Pierre,&nbsp;Ann Rancourt,&nbsp;Maude Fillion,&nbsp;Sachiko Sato","doi":"10.1096/fj.202500196R","DOIUrl":"10.1096/fj.202500196R","url":null,"abstract":"<p>N-acetylglucosamine (GlcNAc) is an endogenous compound with intracellular concentration closely linked to the biosynthesis of acetyllactosamine-rich N-linked oligosaccharides. These oligosaccharides interact with mammalian lectin galectin-3, mediating cell surface receptor dynamics as well as cell–cell and cell-extracellular matrix interactions. Our previous and recent studies suggest that GlcNAc, in conjunction with galectin-3, enhances muscle regeneration in vitro. We have also demonstrated that intraperitoneal GlcNAc administration improves muscle strength in <i>mdx</i> mice, a murine model of Duchenne muscular dystrophy (DMD). Here, we show that oral administration of GlcNAc significantly improves the spontaneous locomotor activity of <i>mdx</i> mice. Daily treatment with United States Pharmacopeia-grade GlcNAc at doses of 0.6, 1.2, 1.8, and 2.4 g/kg body weight for 35 days significantly enhanced nocturnal spontaneous locomotor activity, with the 1.2 g/kg body weight dose (equivalent to 0.144 g/kg body weight in humans) reducing damages of extensor digitorum longus muscle by nearly 50%. Although consecutive forced exercises, specifically horizontal and downhill treadmill running, reduced GlcNAc-mediated improvement, mice treated with 0.6 and 1.2 g/kg body weight still showed increased overall spontaneous locomotor activity under this condition, despite the lack of protection against repeated eccentric contraction-induced injury. These findings suggest that GlcNAc enhances overall muscle health, possibly through mechanisms other than direct protection from muscle injury. One possible contributing mechanism may involve enhanced muscle repair or regeneration, as suggested by our related in vitro myogenesis work. Notably, co-administration of GlcNAc with prednisolone, a corticosteroid commonly prescribed for DMD patients, further enhanced spontaneous locomotor improvement in <i>mdx</i> mice compared to prednisolone alone. These findings suggest that GlcNAc has the potential to improve the clinical status of DMD patients, either as a monotherapy or in combination with corticosteroids.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500196R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058056","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":"Primary Cilia-Mediated Hedgehog Signaling Regulates Cell Fate During ER Stress-Induced Life or Death Decisions","authors":"Jia Xu,&nbsp;Yongli Zhang,&nbsp;Junmin Pan","doi":"10.1096/fj.202500391RR","DOIUrl":"10.1096/fj.202500391RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Primary cilia play critical roles in development and physiology. The unfolded protein response (UPR), triggered by endoplasmic reticulum (ER) stress, is a fundamental cellular process. However, whether and how ER stress influences ciliary assembly and function remain poorly understood. Here, we demonstrate that ER stress promotes ciliogenesis and hedgehog (HH) signaling by upregulating cholesterol levels, thereby alleviating cellular damage. IRE1 and PERK, sensors of ER stress, positively regulate ciliogenesis by enhancing the trafficking of preciliary vesicles through upregulation of cellular cholesterol levels via activation of SREBP2. Furthermore, the cholesterol content in the ciliary membrane also increases during ER stress, leading to enhanced ciliary recruitment of Smoothened (SMO) and activation of HH signaling. The activation of HH signaling via primary cilium is crucial for protecting cells from stress-induced damage. Our findings unveil a pivotal role of cilia-mediated hedgehog signaling in cell fate determination under ER stress.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 18","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145058066","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}