The FASEB Journal最新文献

{"title":"Podoplanin-TGF-β1 Autocrine Loop: Pivotal Regulator of Islet Stellate Cell Activation via Cell Deformation, Orchestrating Islet Fibrosis in Diabetes","authors":"Xiaohang Wang,&nbsp;Qianqian Wang,&nbsp;Yang Yuan,&nbsp;Chengming Ni,&nbsp;Zhensheng Cai,&nbsp;Shanhu Qiu,&nbsp;Tingting Li,&nbsp;Yang Chen,&nbsp;Jinbang Wang,&nbsp;Huan Wang,&nbsp;Vladmir Carvalho,&nbsp;Zilin Sun,&nbsp;Lijie Liu","doi":"10.1096/fj.202500760R","DOIUrl":"10.1096/fj.202500760R","url":null,"abstract":"<div>\u0000 \u0000 <p>The activation of islet stellate cells (ISCs) plays an important role in islet fibrosis, which leads to impaired islet function. While our previous work showed that the expression of the <i>Pdpn</i> gene was significantly increased in activated ISCs, it remains unknown whether <i>Pdpn</i> is responsible for islet fibrosis. This study was aimed at elucidating its function on islet fibrosis, along with the exploration of the underlying mechanisms. Then, diabetic mice were used for in vivo studies, while primary ISCs were used for in vitro experiments. Podoplanin (PDPN) expression was manipulated using gene knockdown and overexpression techniques. Beta-cell function was assessed by insulin secretion and glucose tolerance tests. Islet fibrosis was evaluated by quantifying extracellular matrix deposition and ISCs activation markers using histological staining and immunohistochemistry, respectively. The effects of advanced glycation end products (AGEs) and TGF-β1 on PDPN expression and the corresponding mechanisms of ISCs activation were investigated. Finally, it was found that knocking down PDPN in diabetic mice led to reduced ISCs activation and islet fibrosis, accompanied by improved insulin expression and lower fasting blood glucose. AGEs were found to induce PDPN expression in ISCs. The overexpression of PDPN triggers the activation of ISCs via cell deformation and TGF-β1 secretion. Interestingly, TGF-β1 in turn activates the TGF-β1/SMAD2/3 pathway by binding to TGF-βRI, inducing the expression of PDPN and the activation of ISCs. In summary, PDPN regulates the activation of ISCs through a mechanism involving cell deformation and a PDPN-TGF-β1 autocrine feedback loop, thereby significantly contributing to islet fibrosis in diabetes.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930073","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":"GNAQ p.R183Q Endothelial Cells Fail to Align in Response to Laminar Shear Stress and Exhibit Increased Expression of MAPK, Inflammation, and Cell Adhesion Genes","authors":"Sana Nasim,&nbsp;Biju Issac,&nbsp;Qianyi Ma,&nbsp;Liang Sun,&nbsp;Joyce Bischoff","doi":"10.1096/fj.202502180R","DOIUrl":"10.1096/fj.202502180R","url":null,"abstract":"<div>\u0000 \u0000 <p>Vascular malformations are caused by germline or somatic mutations. A key research focus is the influence of laminar shear stress (LSS) on the development of these malformations. In this study, we explore how endothelial cells (EC) with the <i>GNAQ</i> p.R183Q somatic mutation, which is found in 90% of syndromic and non-syndromic capillary malformations (CM), respond to increasing levels of LSS. Our findings show that in contrast to control EC (EC-WT), the mutant EC (EC-R183Q) fail to align under LSS conditions. RNA sequencing revealed altered gene expression in EC-R183Q exposed to LSS, specifically in pathways related to MAPK, apoptosis, inflammation, and cell adhesion. These results suggest impaired mechanosensory responses in <i>GNAQ</i> p.R183Q endothelium that may contribute to vascular dysfunction in CM.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930071","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":"Gut Microbiota-Derived Metabolites Orchestrate Metabolic Reprogramming in Diabetic Cardiomyopathy: Mechanisms and Therapeutic Frontiers","authors":"Jing-yu Jin,&nbsp;Xin-yu Yang,&nbsp;Ru Feng,&nbsp;Meng-liang Ye,&nbsp;Hui Xu,&nbsp;Jing-yue Wang,&nbsp;Jia-chun Hu,&nbsp;Heng-tong Zuo,&nbsp;Jin-yue Lu,&nbsp;Jian-ye Song,&nbsp;Yi Zhao,&nbsp;Yan Wang,&nbsp;Qian Tong","doi":"10.1096/fj.202501579RR","DOIUrl":"10.1096/fj.202501579RR","url":null,"abstract":"<p>Diabetic cardiomyopathy (DCM) is a major cardiovascular complication of diabetes mellitus, characterized by myocardial structural and functional abnormalities in the absence of overt coronary artery disease or hypertension. A growing body of evidence implicates the gut microbiota and its metabolites as key modulators of systemic metabolic homeostasis, influencing energy metabolism, inflammation, and oxidative stress. The gut microbiota emerges as a novel regulator of cardiac remodeling and metabolic reprogramming in DCM through the gut–heart axis. This review aims to synthesize current mechanistic insights into how gut microbiota and its bioactive metabolites contribute to metabolic reprogramming in DCM. It further evaluates the potential of microbiota-targeted interventions as emerging therapeutic strategies to mitigate disease progression and restore cardiac homeostasis. A narrative, mechanistically focused literature review was conducted using PubMed and Web of Science databases. It covered experimental, preclinical, and translational studies up to April 2025. Articles were selected based on relevance to gut microbial metabolism, host cardiac metabolic pathways, and therapeutic interventions linked to DCM. Gut microbiota-derived metabolites—including short-chain fatty acids (SCFAs), trimethylamine N-oxide (TMAO), bile acids, lipopolysaccharides (LPS), tryptophan catabolites, and hydrogen sulfide—modulate cardiometabolic pathways via epigenetic regulation, altered energy substrate utilization, inflammatory signaling, and mitochondrial oxidative stress. These metabolites influence insulin resistance, lipid accumulation, mitochondrial dynamics, and cardiac fibrosis. Therapeutic strategies such as dietary modulation, probiotics, prebiotics, fecal microbiota transplantation, and drugs like SGLT2 inhibitors and GLP-1 receptor agonists have shown promising effects in modulating gut microbiota composition and alleviating DCM phenotypes in animal models. However, clinical evidence remains limited. The gut microbiota plays a pivotal role in the pathogenesis and potential treatment of DCM through its ability to reprogram host metabolism and inflammation. While preclinical data are compelling, further translational research—including humanized models and multi-omics integration—is required to validate microbiota-targeted therapies for cardiovascular applications. Targeting the microbiota–metabolite axis offers an innovative therapeutic avenue for personalized intervention in diabetic heart disease.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501579RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930098","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":"Chronic Waterborne Exposure to Polystyrene Microplastics Induces Kupffer Cell Polarization Imbalance and Hepatic Lipid Accumulation","authors":"Ting Li,&nbsp;Zhenghong Yao,&nbsp;Yuxin Huang,&nbsp;Ran Li,&nbsp;Lu Zhang,&nbsp;Rucheng Chen,&nbsp;Weijia Gu","doi":"10.1096/fj.202500910RR","DOIUrl":"10.1096/fj.202500910RR","url":null,"abstract":"<p>Microplastics (MPs), particles under 5 mm, are widespread environmental contaminants. Polystyrene (PS), used in many household items, degrades into polystyrene MPs (PS-MPs), which accumulate in the environment. Chronic exposure to waterborne PS-MPs was found to disrupt hepatic lipid metabolism in C57BL/6N mice through inflammatory Kupffer cell polarization and IL-17/NF-κB signaling pathways. While short-term PS-MPs exposure revealed preferential accumulation in the liver and testes, long-term exposure (9–12 weeks) induced significant increases in body fat percentage and hepatic lipid deposition independent of dietary changes. Mechanistically, chronic PS-MPs exposure promoted Kupffer cell polarization toward pro-inflammatory M1 phenotypes, accompanied by upregulated IL-17 expression and suppressed anti-inflammatory cytokines. Western blot analysis demonstrated concurrent elevation of lipid synthesis markers with reduced lipid oxidation and transport proteins. These findings established that PS-MPs accumulation drives hepatic steatosis through dual mechanisms of macrophage-mediated inflammation and impaired lipid homeostasis pathways.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202500910RR","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144930095","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":"ESA VIVALDI Dry Immersion Microgravity Simulations Induce Increases in Immune Biomarkers Associated With Physical and Psychological Stress, and Sex-Specific Factors","authors":"Pauline Jacob,&nbsp;Adrien Robin,&nbsp;Nastassia Navasiolava,&nbsp;Marc-Antoine Custaud,&nbsp;Stéphanie Ghislin,&nbsp;Marie-Pierre Bareille,&nbsp;Rebecca Billette De Villemeur,&nbsp;Inês Antunes,&nbsp;Angelique Van Ombergen,&nbsp;Guillemette Gauquelin-Koch,&nbsp;Jean-Pol Frippiat","doi":"10.1096/fj.202502198R","DOIUrl":"10.1096/fj.202502198R","url":null,"abstract":"<p>With future manned space projects involving missions of unprecedented duration, multisystem deconditioning induced by spaceflight could seriously affect the well-being and health of astronauts. Safe and easily determined in-flight biomarkers are therefore needed to monitor health status. In this study, we simulated space deconditioning with a 5-day dry immersion (DI) of 18 healthy women and 19 healthy men and evaluated the effects of this protocol on three biomarkers: the neutrophil-to-lymphocyte ratio (NLR), the granulocyte-to-lymphocyte ratio (GLR) and the platelet-to-lymphocyte ratio (PLR). Increases in all three ratios were observed in both men and women, as also observed at the end of a space mission or after exposure to simulated microgravity. These increases were associated with physical and psychological stress in both sexes. Furthermore, our work suggested a positive link between NLR increase and cardiovascular system alteration in women, whereas in men, there would be a positive relationship between NLR, GLR, PLR, and inflammation. Thus, in addition to physical and psychological stress, sex-specific factors could contribute to increases in NLR, GLR, and PLR ratios during DI. As for the increase in PLR, it did not predict the development of long-lasting immune diseases during DI, in contrast to 2 months of head-down tilt bed rest (HDBR), another spaceflight analog. These data show that the NLR, GLR, and PLR ratios are promising biomarkers that deserve further study to determine the relationships between their increase and microgravity-induced deconditioning. These dry immersion investigations are registered at clinicaltrials.gov as NCT05043974 for women and NCT05493176 for men.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202502198R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144927664","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":"circHMGCS1 Promotes the Progression of NSCLC by Regulating the HuR/SFPQ/TNF Pathway","authors":"Jiayue An,&nbsp;Weimiao Sun,&nbsp;Chenhui Ti,&nbsp;Yulong Mu,&nbsp;Baohui Yin,&nbsp;Qin Wang,&nbsp;Xia Zhang,&nbsp;Yan Liang,&nbsp;Hongfang Sun,&nbsp;Shuyang Xie,&nbsp;Youjie Li","doi":"10.1096/fj.202501444RR","DOIUrl":"10.1096/fj.202501444RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Among lung cancers, non-small-cell lung cancer (NSCLC) is the most common type. Evidence demonstrates that abnormal expression of circular RNAs (circRNAs) is associated with cancer progression through interactions with RNA-binding proteins (RBPs). Therefore, further elucidation of the role of circular RNAs may provide new therapeutic targets for NSCLC patients. This study identified a novel circRNA, circHMGCS1 (hsa_circ_0072387), using circRNA microarrays. Validation and characterization of circHMGCS1 were performed by Sanger sequencing and RNase R treatment. CCK-8 and Transwell assays were used to determine the function of circHMGCS1 in cell proliferation and migration. The interaction between circHMGCS1 and human antigen R (HuR) protein was verified by RNA pull-down and RNA immunoprecipitation (RIP) assays. The effect of HuR on the stability of splicing factor proline- and glutamine-rich (SFPQ) mRNA was verified by dual-luciferase reporter gene assay and actinomycin D treatment. We found that circHMGCS1 was upregulated in NSCLC cells and tissues. Mechanistically, circHMGCS1 binds to HuR, and its high expression stabilizes HuR by inhibiting its ubiquitin-mediated degradation. HuR was shown to mediate the stability of SFPQ mRNA and promote the progression of NSCLC. RNA sequencing analysis indicated that SFPQ may inhibit apoptosis by suppressing tumor necrosis factor (TNF) signaling. This study revealed that circHMGCS1 contributes to NSCLC progression by stabilizing oncogenic HuR and promoting post-transcriptional upregulation of SFPQ, highlighting its potential as a diagnostic and prognostic biomarker for NSCLC.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144927580","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":"Correction to “Psrc1 Ensures Proper Spindle Assembly and Chromosome Segregation During Mouse Oocyte Maturation”","authors":"","doi":"10.1096/fj.202503087","DOIUrl":"10.1096/fj.202503087","url":null,"abstract":"<p>The citation “W. Xin-Jie, W. Kang-Na, L. Yu-Qing, et al., “ Psrc1 Ensures Proper Spindle Assembly and Chromosome Segregation During Mouse Oocyte Maturation,” The FASEB Journal 39, no. 16 (2025): e70928, https://doi.org/10.1096/fj.202501813R” is incorrect.</p><p>\u0000 This should have read: “ <span>X.-J. Wang</span>, <span>K.-N. Wei</span>, <span>Y.-Q. Liu</span>, et al., “ <span>Psrc1 Ensures Proper Spindle Assembly and Chromosome Segregation During Mouse Oocyte Maturation</span>,” <i>The FASEB Journal</i> <span>39</span>, no. <span>16</span> (<span>2025</span>): e70928, https://doi.org/10.1096/fj.202501813R.”\u0000 </p><p>In the original publication of the article, there were multiple instances where the first and last names of the authors were inverted.</p><p>The list of authors “Wang Xin-Jie ^1,2, Wei Kang-Na ^1,3, Liu Yu-Qing ¹, Zeng Zhao-Cheng ^1,4, Liang Hui-Sheng ^1,5, Jiang Jiang ^1,4, Zeng Li-Xin ^1,3, Wang Hai-Long ¹” was incorrect.</p><p>This should have read: “Xin-Jie Wang ^1,2, Kang-Na Wei ^1,3, Yu-Qing Liu ¹, Zhao-Cheng Zeng ^1,4, Hui-Sheng Liang ^1,5, Jiang Jiang ^1,4, Li-Xin Zeng ^1,3, Hai-Long Wang ¹.^”</p><p>Correspondence for the corresponding author “Wang Hai-Long (<span>[email protected]</span>)” was incorrect.</p><p>Correspondence should have read: “Hai-Long Wang (<span>[email protected]</span>)”.</p><p>The Author Contributions “Wang Hai-Long designed the study and applied for Research Ethics Board approval. Wang Xin-Jie completed all the experiments during the study. Wei Kang-Na and Liu Yu-Qing drafted the manuscript. Zeng Zhao-Cheng, Liang Hui-Sheng, and Jiang Jiang completed the data analysis. Zeng Li-Xin participated in the editing of the article and had complete access to the study data” was incorrect.</p><p>The Author Contributions should have read: “Hai-Long Wang designed the study and applied for Research Ethics Board approval. Xin-Jie Wang completed all the experiments during the study. Kang-Na Wei and Yu-Qing Liu drafted the manuscript. Zhao-Cheng Zeng, Hui-Sheng Liang, and Jiang Jiang completed the data analysis. Li-Xin Zeng participated in the editing of the article and had complete access to the study data.”</p><p>We apologize for this error.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202503087","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144927583","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":"A Novel CHRM3-Driven Preclinical Model of Irritable Bowel Syndrome","authors":"Junmin Yang,&nbsp;Xueyang Li,&nbsp;Chong Wang,&nbsp;Xiaoyu Yang,&nbsp;Pan Zheng,&nbsp;Jie Liang,&nbsp;Li Zhang,&nbsp;Liang Xia,&nbsp;Jianhua Wan","doi":"10.1096/fj.202501572R","DOIUrl":"10.1096/fj.202501572R","url":null,"abstract":"<div>\u0000 \u0000 <p>Irritable bowel syndrome (IBS) is a prevalent functional gastrointestinal disorder that significantly reduces patients' quality of life. However, current animal models have limitations in replicating the complex pathophysiology of IBS. In this study, we successfully developed a mouse model by mating intestinal epithelium-specific Cre tool mice with chemically modified human muscarinic acetylcholine receptor 3 (hCHRM3) mice, resulting in specific expression of the hCHRM3 in the intestinal epithelial cells. Activation of the hCHRM3 with clozapine-N-oxide (CNO) mimicked IBS attacks. The model mice exhibited typical IBS symptoms such as diarrhea, pain, and visceral hypersensitivity, along with pathological changes like intestinal edema and inflammatory cell infiltration, and disruption of the intestinal mucosal barrier. RNA sequencing revealed significant differentially expressed genes between the model and control groups, with KEGG and GO enrichment analyses indicating significant enrichment of immune and inflammation-related pathways. Additionally, the model mice showed increased levels of short-chain fatty acids and imbalances in the diversity and composition of the gut microbiota. This new IBS mouse model effectively simulates the symptoms and pathological processes of human IBS, providing a powerful tool for in-depth research into the pathogenesis of IBS and the development of therapeutic strategies.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144927528","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":"Metabolome-Wide Mendelian Randomization Identifies Valine as a Potential Mediator of the Effect of Obesity on Pancreatic Cancer Risk","authors":"Kui Li,&nbsp;Chao Zhang,&nbsp;Cheng Yan","doi":"10.1096/fj.202501757R","DOIUrl":"10.1096/fj.202501757R","url":null,"abstract":"<div>\u0000 \u0000 <p>Obesity is a well-established risk factor for pancreatic cancer (PC), yet the underlying metabolic mechanisms that link obesity to increased PC risk remain unclear. This study aims to identify the specific metabolites mediating the relationship between obesity and pancreatic cancer. A two-sample two-step Mendelian randomization (MR) approach was used to determine the causal effects of circulating metabolites on PC risk and the causal effects of body mass index (BMI) on potential metabolites. Independent datasets were employed to validate the results from both steps. The mediation effect of the potential metabolites was quantified using the product of coefficients approach. Our study identified 55 circulating metabolites associated with PC risk through MR analysis, with no evidence of pleiotropy, heterogeneity, or reverse causality. Among them, 5 metabolites, including valine, showed a causal association with BMI. To validate our findings, Step 1 was replicated using an independent pancreatic cancer dataset from the UK Biobank, replacing the FinnGen cohort, while Step 2 was validated by substituting whole-body fat mass for BMI as the exposure; both analyses consistently confirmed the association with valine. Mediation analysis demonstrated that circulating valine levels partially mediated the effect of BMI on PC risk. The estimated mediated effect via valine was <i>β</i> = 0.064, corresponding to an approximate mediated proportion of 19.01%. This study reveals valine as a crucial metabolic mediator linking obesity to PC risk. The findings also underscore the complex interplay between obesity, metabolites, and cancer, offering new insights and avenues for PC research and treatment.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144927582","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":"KLF9 Inhibits Brain Metastasis of Non-Small Cell Lung Cancer by Regulating Ceramide Synthase 1 Synthesis","authors":"Yingqiu He,&nbsp;Junfan Pan,&nbsp;Sufang Chen,&nbsp;Ying Lin,&nbsp;Peiwei She,&nbsp;Yusheng Chen,&nbsp;Nengluan Xu,&nbsp;Hongru Li","doi":"10.1096/fj.202501354R","DOIUrl":"10.1096/fj.202501354R","url":null,"abstract":"<p>The regulatory mechanisms driving brain metastasis (BM) in non-small cell lung cancer (NSCLC) are complex, with Ceramide synthase 1 (Cers1) playing a critical role. However, the upstream factors controlling Cers1 expression remain unclear. Additionally, Kruppel-like factor 9 (KLF9) has been implicated as a potential tumor suppressor transcription factor (TF) in lung cancer. Our study aims to explore the physiological effects and molecular mechanisms of Cers1 upstream regulatory TFs in NSCLC BM, focusing on the link between KLF9 and Cers1. TFs regulating Cers1 expression were screened via GENECARD and UCSC databases. KLF9 expression and survival analysis in NSCLC were analyzed using TCGA and GEO data sets. Dual-luciferase assays were conducted to investigate the specific binding site of KLF9 on the Cers1 promoter. KLF9 genetic modulation impact on NSCLC BM was assessed through in vitro assays for proliferation, migration, and invasion, along with in vivo orthotopic xenograft models to evaluate tumor growth and metastasis. Our study revealed a significant downregulation of KLF9 in vitro, correlating with poor prognosis. KLF9 has a direct positive transcriptional regulation on Cers1, particularly on its promoter region (−711 nt/+22 nt). In vitro, KLF9 overexpression inhibited the ability of cells to penetrate a blood–brain barrier model. Moreover, in vivo experiments demonstrated a marked suppression of BM tumor formation upon KLF9 expression. This study reports KLF9's direct control over Cers1 expression by acting on its promoter. KLF9 demonstrates inhibitory effects on NSCLC BM, presenting a promising therapeutic avenue for NSCLC BM treatment.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"39 17","pages":""},"PeriodicalIF":4.2,"publicationDate":"2025-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://faseb.onlinelibrary.wiley.com/doi/epdf/10.1096/fj.202501354R","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144927579","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}