The FASEB Journal最新文献

{"title":"UGA4 and YBR062C Regulate Oxidative Stress Tolerance Under Heavy Metal Toxicity","authors":"Mustafa Al-gafari,&nbsp;Houman Moteshareie,&nbsp;Thomas D. D. Kazmirchuk,&nbsp;Jiashu Wang,&nbsp;Sarah Takallou,&nbsp;Parvin Khosravifar,&nbsp;Mohsen Hooshyar,&nbsp;Bahram Samanfar,&nbsp;Ashkan Golshani","doi":"10.1096/fj.202503701R","DOIUrl":"10.1096/fj.202503701R","url":null,"abstract":"<p>Heavy metals impose a major cellular stress by promoting protein dysfunction and the accumulation of reactive oxygen species (ROS). In <i>Saccharomyces cerevisiae</i>, the glutathione S-transferase Ure2p is a key determinant of resistance to metal-induced oxidative stress and can be synthesized through a stress-responsive, cap-independent internal ribosome entry site (IRES) in the <i>URE2</i> 5′ UTR. Much has been learned about the cellular responses to heavy metal exposure; however, the mechanistic details of how response genes are regulated in response to stress require further investigation. Here, we identify two previously unrecognized contributors to heavy metal tolerance, <i>UGA4</i>, a 4-aminobutyric acid GABA permease, and <i>YBR062C</i>, a poorly characterized gene previously linked to filamentous growth. Deletion of <i>UGA4</i> or <i>YBR062C</i> caused notable sensitivity when cells were exposed to sub-inhibitory concentrations of cadmium (Cd), arsenite (As(III)), and nickel (Ni), with colony-forming units reduced by approximately 50%–80% relative to the wild-type strain. Genetic analysis positioned both genes in the <i>URE2</i> pathway. Double mutants <i>ure2Δ uga4Δ</i> and <i>ure2Δ ybr062cΔ</i> were not more sensitive than the single mutant <i>ure2Δ</i>. <i>URE2</i> overexpression restored metal resistance in <i>uga4Δ</i> and <i>ybr062cΔ</i> backgrounds, whereas <i>UGA4</i> or <i>YBR062C</i> overexpression did not rescue <i>ure2Δ</i>. Mechanistically, <i>UGA4</i> and <i>YBR062C</i> acted post-transcriptionally. <i>URE2</i> mRNA abundance was unchanged, but Ure2p protein levels were reduced, particularly under Cd stress. Polysome profiling revealed decreased ribosomal association of <i>URE2</i> mRNA in both mutants, and a URE2-IRES–dependent β-galactosidase reporter showed approximately 80% lower activity without affecting cap-dependent translation or altering reporter mRNA levels. Together, these data demonstrate that <i>UGA4</i> and <i>YBR062C</i> promote heavy metal tolerance by enabling IRES-mediated translation of <i>URE2</i> mRNA.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12970579/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147379272","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":"Dysbiosis in the Gut-Liver Axis Is Associated With Low Bone Mass During Murine Cholestasis","authors":"Brooke Hutchison,&nbsp;Jamie Fornsaglio,&nbsp;Ridgeway Case IV,&nbsp;Pam Cornuet,&nbsp;Fu-Ying Qin,&nbsp;Xiaochao Ma,&nbsp;Kari Nejak-Bowen,&nbsp;Matthew D. Carson","doi":"10.1096/fj.202502976R","DOIUrl":"10.1096/fj.202502976R","url":null,"abstract":"<p>The gut-liver axis is the bidirectional relationship between the gut microbiota and the liver. Dysbiosis in the gut-liver axis and disrupted bile acid homeostasis contribute to cholestatic liver disease pathogenesis. Patients afflicted with cholestasis have accelerated bone loss, a higher incidence of fractures, and are at risk of developing osteoporosis. However, the mechanisms underlying bone loss are largely unknown. The study purpose was to investigate the role of the gut-liver axis and bile acid signaling on skeletal homeostasis during cholestasis. Male C57BL/6J specific-pathogen-free mice were administered 3,5-diethoxycarbonyl-1,4-dihydrocollidine from age 11 to 15 weeks to induce cholestasis. 16s rDNA sequencing was performed on colonic contents. Livers were processed for qRT-pCR. Trabecular and cortical bone were analyzed by micro-CT. Osteoclast/osteoblast outcomes were determined by histomorphometry. Bile acid concentrations in serum and bone marrow were assessed by mass spectrometry. MC3T3-E1 and RAW 264.7 cells were stimulated with bile acids at concentrations found in the bone marrow to determine their effects on osteoblasts and osteoclasts. Cholestatic mice had less bone mass than controls, attributed to increases in osteoclasts and decreases in osteoblasts. Following cholestatic injury, mice show dysbiotic shifts in their colonic bacteriome, increased expression of hepatic bile acid efflux transporters, and elevated bone marrow bile acids. In vitro, bile acids from the bone marrow of cholestatic mice suppressed osteoblastogenesis and promoted osteoclastogenesis, which was rescued by stimulating cells with a farnesoid X receptor agonist. This study introduces the gut-liver axis as a novel regulator of skeletal homeostasis during cholestatic liver disease through dysregulated bile acid signaling.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12970511/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147379667","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":"Parthenolide Attenuates Skeletal Muscle Atrophy Through Regulation of Protein Homeostasis and Inhibition of Inflammation","authors":"Yu Bai,&nbsp;Weiqing Li,&nbsp;Yahong Lu,&nbsp;Hehuan Lai,&nbsp;Lin Ye,&nbsp;Kechi Li,&nbsp;Chendi Wang,&nbsp;Yi Ding,&nbsp;Wenhao Li,&nbsp;Yitao Chen,&nbsp;Keping Gan,&nbsp;Zhenzhong Chen,&nbsp;Dengwei He","doi":"10.1096/fj.202504024RR","DOIUrl":"10.1096/fj.202504024RR","url":null,"abstract":"<p>Skeletal muscle atrophy is a complex condition associated with various diseases, including chronic inflammation, and significantly impairs quality of life. Parthenolide, a bioactive compound derived from <i>Tanacetum parthenium</i> (feverfew), is well known for its anti-inflammatory properties, but its potential therapeutic effects on muscle atrophy remain underexplored. In this study, we evaluated the protective effects of parthenolide against muscle atrophy in both in vitro and in vivo models. Using TNF-α-treated C2C12 myotubes and a lipopolysaccharide (LPS)-induced muscle atrophy in mice, we assessed the impact of parthenolide through histology, functional assays, and molecular analyses. Our results demonstrated that parthenolide promoted myoblast differentiation and alleviated TNF-α-induced myotube atrophy by restoring myosin heavy chain (MyHC) expression and inhibiting muscle-specific ubiquitin ligases MuRF1 and MAFbx. Mechanistically, parthenolide regulates protein homeostasis by activating the Akt–mTOR pathway, inhibiting FoxO transcription factors, and suppressing inflammation via NF-κB inhibition. In vivo, parthenolide effectively reduced LPS-induced muscle mass loss, muscle fiber atrophy, and grip strength decline, with improvements linked to the downregulation of atrophy markers and the preservation of MyHC levels in muscle tissue. These findings indicate that parthenolide mitigates skeletal muscle atrophy through dual regulation of protein homeostasis and inflammation, highlighting its potential as a novel therapeutic agent for muscle-wasting disorders such as sarcopenia.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12970493/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147379266","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":"Extracellular Vesicles Secreted by Human Microglia Support Blood–Brain Barrier Function Under Both Physiological and Inflammatory Conditions","authors":"Agnė Pociūtė,&nbsp;Kotryna Milovanovaitė,&nbsp;Agnė Jokubauskytė,&nbsp;Augustas Pivoriūnas","doi":"10.1096/fj.202504928R","DOIUrl":"10.1096/fj.202504928R","url":null,"abstract":"<div>\u0000 \u0000 <p>Brain endothelial cells (BECs) are essential for maintaining central nervous system homeostasis through the formation of the blood–brain barrier (BBB), whose integrity depends on continuous signaling from neighboring cells of the neurogliovascular unit. Although microglia are positioned in close proximity to cerebral vessels, their contribution to BBB regulation remains poorly defined. Here, we investigated the impact of paracrine signals from human microglia on BBB function under homeostatic and inflammatory conditions. Using a non-contact co-culture system with human induced pluripotent stem cell-derived BECs, we found that unstimulated microglia enhanced BBB integrity, as evidenced by increased transendothelial electrical resistance (TEER), upregulation of the tight junction proteins claudin-5, occludin, and ZO-1, and promotion of BEC proliferation. In contrast, TNFα-activated microglia did not support barrier integrity. Conditioned media from unstimulated microglia recapitulated the TEER-enhancing effects, whereas extracellular vesicle (EV)-depleted conditioned media failed to do so, implicating EVs as key mediators. Purified EVs from both unstimulated and TNFα-activated microglia promoted proliferation, increased TEER, elevated tight junction protein expression, and, notably, mitigated TNFα-induced barrier disruption by preserving TEER, endothelial proliferation, and tight junction continuity. Together, these findings identify microglia-derived EVs as potent positive regulators of BBB integrity and demonstrate that, even under inflammatory activation, microglial EVs retain the capacity to support endothelial barrier function. This work reveals a previously underappreciated mechanism by which microglia contribute to vascular homeostasis and suggests microglial EVs as potential therapeutic targets for preserving BBB integrity in neuroinflammatory diseases.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 6","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147379654","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":"Methylglyoxal Affects Dopamine Homeostasis in SH-SY5Y Cells Through the Modulation of miR-190a and miR-214","authors":"Alessandra Croce,&nbsp;Paola Mirra,&nbsp;Francesca Chiara Pignalosa,&nbsp;Federica Zatterale,&nbsp;Immacolata Prevenzano,&nbsp;Domenico Conza,&nbsp;Luca Ulianich,&nbsp;Claudia Miele,&nbsp;Francesco Beguinot,&nbsp;Francesca Fiory","doi":"10.1096/fj.202501805R","DOIUrl":"10.1096/fj.202501805R","url":null,"abstract":"<p>Dopamine (DA) homeostasis is crucial for several relevant body functions, including cognition. Diabetes mellitus (DM) is characterized by both cognitive decline and dopaminergic dysfunction. Methylglyoxal (MGO), a reactive neurotoxic dicarbonyl, which accumulates in DM, induces dopaminergic dysfunction, contributing to DA depletion, and is associated with cognitive deficit. However, the molecular mechanisms underlying MGO impact on dopaminergic function are still unknown. This study aims to clarify how MGO damages the dopaminergic system, analyzing the contribution of miRNAs in its deleterious effect in SH-SY5Y cells. We found that treatment with MGO significantly reduces the intracellular DA content, increasing the expression of proteins known to negatively affect DA amount, such as COMT (Catechol-O-methyltransferase), MAO (Monoamine oxidase), and α-Syn (α-synuclein), encoded by the SNCA gene. This was paralleled by a significant reduction in the expression of miR-190a and miR-214, known to be regulated by MGO in other cellular models. We found, by TARGETSCAN analysis, that these two miRNAs are predicted regulators of COMT and SNCA. Gain- and loss-of-function experiments highlighted that these miRNAs are able to modulate the expression of these proteins. We also showed that COMT is a direct target of both miR-190a and miR-214, while SNCA is a direct target of miR-190a and an indirect target for miR-214. Importantly, the transfection of miR-190a and miR-214 specific mimics reverted MGO effects on COMT and α-Syn expression and restored DA intracellular content. Thus, these miRNAs could represent innovative pharmacological targets for the treatment of DM-associated dopaminergic dysfunction and cognitive decline.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12966953/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147370601","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 Porcine Colitis Model Recapitulates the Visceral Adipose Metabolic Reprogramming of Human Ulcerative Colitis","authors":"Yu Peng,&nbsp;Qipin Lv,&nbsp;Xu Han,&nbsp;Chenyu Zhao,&nbsp;Haocen Luo,&nbsp;Jiayu Tang,&nbsp;Yifan Jiang,&nbsp;Tianwen Wu,&nbsp;Shulin Yang,&nbsp;Yanfang Wang,&nbsp;Cong Tao","doi":"10.1096/fj.202504741R","DOIUrl":"10.1096/fj.202504741R","url":null,"abstract":"<div>\u0000 \u0000 <p>Adipose tissue dysfunction is integral to the pathophysiology of ulcerative colitis (UC), yet the conservation of adipose immunometabolic responses across species remains unclear. Here, we employed a comparative transcriptomic approach to analyze adipose remodeling in dextran sulfate sodium (DSS)-induced porcine and murine colitis models alongside human UC datasets. We report that intestinal inflammation induced widespread adipocyte atrophy and triggered a convergent inflammatory response across physiologically distinct visceral and subcutaneous depots. Mechanistically, this remodeling was defined by a systemic suppression of fatty acid synthesis pathways. Importantly, the expression levels of key lipogenic enzymes were negatively correlated with the severity of colonic inflammation, indicating that intestinal injury directly dictates the magnitude of lipogenesis inhibition. Cross-species alignment revealed a critical distinction: while murine visceral fat exhibited fatty acid metabolism activation, the porcine response mirrored the fatty acid metabolism downregulation observed in human patients. These results identify a fundamental species-specific difference and establish the porcine model as a translational tool, which faithfully replicates the atrophy and fatty acid metabolism suppression characteristic of human inflammatory bowel disease.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147367160","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":"Overproduction of 42 Amino Acids Long Amyloid Beta Leads to Activation of Secretory Autophagy and Development of Drusen-Like Structures Originating From Retinal Pigment Epithelium","authors":"Johanna Ruuth,&nbsp;Toni Tamminen,&nbsp;Elisa Toropainen,&nbsp;Heikki Tanila,&nbsp;Juha M. T. Hyttinen,&nbsp;Tarja Malm,&nbsp;Kai Kaarniranta,&nbsp;Ali Koskela","doi":"10.1096/fj.202502464RRR","DOIUrl":"10.1096/fj.202502464RRR","url":null,"abstract":"<p>Age-related macular degeneration (AMD) is a global vision threatening disease affecting the macular region of the retina. AMD is classified into two forms: dry and wet AMD. There are no effective treatment options available for dry AMD (80% of cases). The cellular pathology includes oxidative stress and dysfunctional autophagy challenging the homeostasis of the retinal pigment epithelial (RPE) cells. Clinical findings include the formation of drusen deposits beneath the RPE cells consisting of 42 amino acids long amyloid beta (Aβ) among other components. However, the origin of drusen remains elusive. The 5xFAD (familiar Alzheimer's disease) mouse model of Alzheimer's disease produces abundant levels of Aβ making it an interesting model to study the possible relationship of Aβ to the formation of extracellular deposits and AMD-like pathology. An immunohistology analysis of the 5xFAD mouse model showed accumulation of autophagic markers SQSTM1 (sequestosome 1) and ubiquitin in the RPE. Concurrently, the markers of secretory autophagy enabling the delivery of the intracellular material to the extracellular lumen were upregulated. Aβ, SQSTM1, ubiquitin, catalase, and TRIM16 (tripartite motif containing 16) shifted age-dependently from intracellular origin to drusen-like deposits beneath the RPE cells. Additionally, classical proteins secreted via secretory autophagy, IL-1β (interleukin 1β), HMGB1 (high mobility group box-1), and ferritin showed similar accumulation which became visible in fundus age-dependently. These findings suggest a role for Aβ in the cellular pathogenesis of AMD. Furthermore, this model showed activated secretory autophagy pathway suggesting a role for Aβ in drusen-like deposition formation.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12965378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147367099","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":"Multi-Omics Data Reveal Estrogen-Driven Dysregulation and Stromal-Epithelial Signaling Alterations in Endometrial Polyps","authors":"Tingwei Chen,&nbsp;Bo Zhang,&nbsp;Zhengli Zhou,&nbsp;Naixue Yang,&nbsp;Ting Liu,&nbsp;Huimei Zhang,&nbsp;Yu Yin,&nbsp;Xiaomei Wu,&nbsp;Xiaozhuo Li,&nbsp;Tao Yu,&nbsp;Xiaodie Wang,&nbsp;Tianqing Li,&nbsp;E. Dong","doi":"10.1096/fj.202504234R","DOIUrl":"10.1096/fj.202504234R","url":null,"abstract":"<p>Endometrial polyps (EPs) are common uterine lesions associated with abnormal uterine bleeding and infertility, yet their pathogenesis remains poorly defined. Here, we performed single-cell RNA sequencing of normal endometrium, para-polyp, and polyp tissues, identifying distinct cellular compositions and transcriptional programs. EPs showed enhanced estrogen signaling and increased epithelial proliferation, accompanied by decreased expression of cytokines and reduced T cell cytotoxicity. Notably, we observed epithelial subpopulations with elevated copy number variations and transcription factors associated with hyperplasia. Cell–cell communication analyzes revealed aberrant stromal-epithelial crosstalk, characterized by upregulated WNT, IGF, and VEGF signaling originating from stromal cells. Spatial transcriptomic analyzes further demonstrated enhanced WNT signaling between stromal and epithelial compartments in endometrial cancer. In vitro glandular organoid models showed that epithelial transcriptional alterations contribute to polyp formation. These findings highlight a critical role of stromal-epithelial interactions in EP development and suggest potential therapeutic targets.</p>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12963523/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147367176","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":"Mechanism of CircBbs9 in Lung Epithelial Cell Ferroptosis in Lipopolysaccharide-Induced Acute Lung Injury","authors":"Hailing Yang,&nbsp;Neng Deng,&nbsp;Kuo Qu,&nbsp;Chunmei Zhang,&nbsp;Min Li","doi":"10.1096/fj.202502894RR","DOIUrl":"10.1096/fj.202502894RR","url":null,"abstract":"<div>\u0000 \u0000 <p>Acute lung injury (ALI) is an acute inflammatory disorder characterized by damage to alveolar epithelium and vascular endothelium. This study explores the mechanism of CircBbs9 (hsa_circ_0079812) in LPS-induced ALI through ferroptosis, aiming to find new therapies for ALI. LPS-induced ALI mouse models and cell models were established. Lung tissue damage was detected via the wet/dry weight ratio of lung tissues, oxygenation index, and histological injury scoring. MDA, GSH, and inflammatory factor levels were evaluated by ELISA. Fe²⁺ content, intracellular ROS, and lipid ROS were detected. CircBbs9, Cblb, ACSL4, GPX4, and miR-671-5p levels were assessed by qRT-PCR and Western blot. CircBbs9 expression was elevated in LPS-induced mouse and cell models. CircBbs9 knockdown reduced pulmonary pathological injury, alleviated ferroptosis, increased cell viability, and reduced ACSL4 expression. CircBbs9 bound to HuR, thereby inhibiting Cblb expression, and decreasing Cblb-mediated ubiquitination and degradation of ACSL4. CircBbs9 competitively bound to miR-671-5p, thereby upregulating ACSL4 expression. Cblb knockdown or miR-671-5p inhibition reversed the suppressive function of CircBbs9 knockdown on ferroptosis in lung epithelial cells. Simultaneous overexpression of HuR and miR-671-5p has superior inhibitory effects on ferroptosis than their individual overexpression. In conclusion, CircBbs9 promotes lung epithelial cell ferroptosis in LPS-induced ALI via the HuR/Cblb/ACSL4 and miR-671-5p/ACSL4 axes.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147357402","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":"Identification of Novel Biomarkers for Crohn's Disease Through the Integration of Machine Learning, Colocalization, and SMR Analysis","authors":"Liang Chen,&nbsp;Jie Hua","doi":"10.1096/fj.202504792R","DOIUrl":"10.1096/fj.202504792R","url":null,"abstract":"<div>\u0000 \u0000 <p>Crohn's disease (CD) is a chronic inflammatory bowel disease with a prevalence rate increasing with time, thus demanding improved diagnostic and therapeutic strategies. The present work focused on identifying the candidate biomarkers for CD diagnosis and treatment. Gene Expression Omnibus (GEO)-derived CD-related gene expression datasets were analyzed. Differential protein–protein interaction network and weighted gene co-expression network analyses were conducted to prioritize the core candidate genes. Multiple machine learning algorithms were used to further refine these candidates. The feature importance of the model with the highest performance was explained using SHapley Additive exPlanations. Additionally, a single-sample gene set enrichment analysis was carried out to evaluate immune cell infiltration and determine the associations with diagnostic markers. In addition, the causal biomarker genes were identified using Bayesian colocalization and the summary data-based Mendelian randomization (SMR) analysis. The combination of glmBoost and random forest machine learning analysis identified five hub genes (<i>CXCL5</i>, <i>SERPINB2</i>, <i>SOCS3</i>, <i>PF4</i>, and <i>IL1R1</i>), which demonstrated robust diagnostic performance for CD. These biomarkers were correlated with the immune cell infiltration patterns indicative of heightened inflammation and Th1/Th17 adaptive immune responses. Colocalization and SMR analyses established a causal association of <i>IL1R1</i> with CD development. This integrative multiomics approach identified the key biomarkers involved in the pathogenic mechanism of CD. The eQTL data based SMR analysis suggested a significant association of <i>IL1R1</i> with CD risk, highlighting its dual effects as a diagnostic biomarker and therapeutic target.</p>\u0000 </div>","PeriodicalId":50455,"journal":{"name":"The FASEB Journal","volume":"40 5","pages":""},"PeriodicalIF":4.2,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147345619","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}