Molecular Medicine最新文献

{"title":"Serum metabolites characterize hepatic phenotypes and reveal shared pathways: results from population-based imaging.","authors":"Juliane Maushagen, Johanna Nattenmüller, Ricarda von Krüchten, Barbara Thorand, Annette Peters, Wolfgang Rathmann, Jerzy Adamski, Christopher L Schlett, Fabian Bamberg, Rui Wang-Sattler, Susanne Rospleszcz","doi":"10.1186/s10020-025-01309-z","DOIUrl":"10.1186/s10020-025-01309-z","url":null,"abstract":"<p><strong>Background: </strong>Steatotic liver disease is a major public health issue, with hepatic iron overload exacerbating fibrotic conditions. This study aimed to identify metabolites associated with hepatic fat and/or iron overload using targeted metabolomics in a population-based cohort.</p><p><strong>Methods: </strong>We used the cross-sectional KORA-MRI study (N = 376 individuals). Hepatic fat and iron content were derived by magnetic resonance imaging, and serum metabolite concentrations were quantified through targeted metabolomics. Associations between 146 metabolites and 40 indicators with hepatic phenotypes were analyzed, adjusted for confounders, and corrected for multiple testing. Formal pathway analyses and mediation analyses including genetic data were conducted. Performance of metabolomics to diagnose steatosis or hepatic iron overload was evaluated using ROC curves, and compared to the fatty liver index (FLI).</p><p><strong>Results: </strong>Overall, 50.8% of participants (mean age 56.4 years) had hepatic steatosis, and 43.6% iron overload. Twelve unique metabolites/indicators (amino acids, lysophosphatidylcholine, acyl-alkyl-phosphatidylcholine), and sums of branched chain and aromatic amino acids, and five lipids, and ratio of acyl-alkyl-phosphatidylcholines to diacyl-phosphatidylcholines were associated with hepatic fat content. 27 metabolites/indicators, including 25 lipids, were associated with hepatic iron content. Addition of these metabolites to the FLI improved diagnosis of steatosis and iron overload nominally. Glycerophospholipid metabolism, phenylalanine, tyrosine and tryptophan biosynthesis and glycerophospholipid metabolism were shared pathway between steatosis and iron overload. Alanine, isoleucine, glutamine and pimeloylcarnitine (C7-DC) mediated effects between genetic variants and hepatic phenotypes.</p><p><strong>Conclusion: </strong>Metabolites were associated with hepatic fat and iron content, shared common pathways, and improved diagnosis of steatosis and iron overload, highlighting the role of iron in hepatic disorders.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"260"},"PeriodicalIF":6.0,"publicationDate":"2025-07-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12282023/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144682796","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"FXR acts as a therapeutic target for ulcerative colitis via suppressing ferroptosis.","authors":"Chenye Zhao, Xiaopeng Li, Mingchao Mu, Liyong Quan, Hang Yuan, Jianbao Zheng, Wei Zhao, Xuejun Sun, Junhui Yu","doi":"10.1186/s10020-025-01305-3","DOIUrl":"10.1186/s10020-025-01305-3","url":null,"abstract":"<p><strong>Background: </strong>The involvement of ferroptosis in ulcerative colitis (UC) is increasingly acknowledged. Several investigations have revealed the various mechanisms by which the farnesoid X receptor (FXR) inhibits ferroptosis in certain diseases; however, its potential modulation of ferroptosis in UC remains unexplored.</p><p><strong>Methods: </strong>The characteristics of FXR expression in colitis were evaluated in the GEO database, patient specimens, and mice with DSS-induced colitis. The role of FXR in ferroptosis was investigated by treating colitis mice with the intestine-restricted FXR agonist fexaramine (Fex) intragastrically. In vitro, Caco-2 cells challenged with RSL3 were used to study the role of FXR in modulating ferroptosis in intestinal epithelial cells (IECs).</p><p><strong>Results: </strong>Fex significantly alleviated symptoms and impeded ferroptosis in mice with DSS-induced colitis. In vitro, Fex rescued Caco-2 cells from RSL3-induced ferroptosis. Mechanistically, FXR was capable of binding to the promoter region of SLC7A11 and upregulated the transcription of SLC7A11, which is beneficial for the synthesis of GSH. Knockdown of SLC7A11 partially abrogated the therapeutic effects of Fex, albeit incompletely. Further investigations revealed that FXR can also increase the protein stability of GPX4 by upregulating the deubiquitinase OTUB1.</p><p><strong>Conclusion: </strong>This study highlights that FXR exerts therapeutic effects against colitis by antagonizing ferroptosis via transactivation of SLC7A11 and increasing GPX4 stability. These results suggest that FXR may be a therapeutic target for treating colitis by antagonizing ferroptosis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"258"},"PeriodicalIF":6.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12273381/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Vitamin D and skin disorders: bridging molecular insights to clinical innovations.","authors":"Qing Li, Hung Chan","doi":"10.1186/s10020-025-01311-5","DOIUrl":"10.1186/s10020-025-01311-5","url":null,"abstract":"<p><p>Growing evidence demonstrates that the immunoregulatory properties of vitamin D are primarily mediated by its active hormonal form, 1,25-dihydroxyvitamin D3 (calcitriol). This secosteroid modulates immune homeostasis through three principal mechanisms: (1) strengthening antimicrobial defense via innate immune potentiation, (2) downregulating pathological inflammatory cascades, and (3) fine-tuning adaptive immunity through lymphocyte differentiation control. Clinically, serum concentrations of the inactive precursor, 25-hydroxyvitamin D3 (25(OH)D3), exhibit an inverse correlation with systemic immune activation and the prevalence/severity of dermatological conditions, including atopic dermatitis, psoriasis, and systemic sclerosis. Suboptimal 25(OH)D3 levels are thus recognized as a modifiable risk factor for such disorders, with vitamin D3 supplementation demonstrating therapeutic potential in improving clinical outcomes. Furthermore, prolonged vitamin D3 supplementation may reduce disease incidence across a spectrum of dermatopathologies. This review synthesizes contemporary mechanistic and clinical insights into vitamin D's immunoregulatory role in cutaneous diseases. To optimize therapeutic efficacy, future clinical trials should incorporate analysis of vitamin D receptor (VDR) polymorphisms as a predictive biomarker in vitamin D3 intervention strategies.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"259"},"PeriodicalIF":6.0,"publicationDate":"2025-07-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12275319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144668018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"12/15-lipoxygenase mediates disturbed flow-induced endothelial dysfunction and atherosclerosis.","authors":"Jia Wei Chen, Shi Li Chen, Xin Rui Wu, Xin Yi Shu, Si Yi Tang, He Yuan, You Ran Li, Jin Wei Quan, Shuo Feng, Rui Yan Zhang, Chen Die Yang, Lin Lu, Xiao Qun Wang","doi":"10.1186/s10020-025-01297-0","DOIUrl":"10.1186/s10020-025-01297-0","url":null,"abstract":"<p><strong>Background: </strong>Disturbed flow regions in the vasculature are predisposed to endothelial dysfunction and atherosclerotic plaque formation. The enzyme 12/15-lipoxygenase (12/15-LOX, encoded by ALOX15) has emerged as a promising therapeutic target for atherosclerosis. However, the relationship between 12/15-LOX and disturbed flow-induced atherosclerosis remains uncharacterized.</p><p><strong>Methods: </strong>Expression of 12/15-LOX in endothelial cells (ECs) exposed to steady flow and disturbed flow was compared in vivo and in vitro. The effect of 12/15-LOX on ECs was analyzed by using ALOX15 knockout mice, EC-specific adeno-associated virus (AAV)-mediated delivery of ALOX15-shRNA, and specific inhibitors. Partial carotid ligation mouse model was established to ascertain the role of 12/15-LOX in ECs under disturbed flow.</p><p><strong>Results: </strong>Compared to steady flow regions, 12/15-LOX was significantly upregulated in ECs at disturbed flow sites. In vivo and in vitro experiments demonstrated that 12/15-LOX promoted disturbed flow-elicited endothelial dysfunction. Mass spectrometry analysis revealed that 12/15-LOX promoted production of 15 s-HETE, a pro-inflammatory eicosanoid metabolite, in ECs exposed to disturbed flow. Furthermore, we showed that disturbed flow activated 12/15-LOX expression through transactivation of its promoter by a mechanosensitive transcription factor sterol regulatory element binding protein 2 (SREBP2). Finally, EC-specific knockdown or inhibition of 12/15-LOX substantially attenuated the development of atherosclerosis in disturbed flow regions.</p><p><strong>Conclusions: </strong>Disturbed flow promoted 12/15-LOX expression via SREBP2, thereby leading to increased pro-inflammatory PUFA metabolites and ECs dysfunction. Targeting at SREBP2-12/15-LOX pathway should provide therapeutic perspectives to attenuate disturbed flow-induced atherosclerosis.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"257"},"PeriodicalIF":6.0,"publicationDate":"2025-07-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12261642/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144637581","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Characterization of Ultra-Short plasma Cell-Free DNA in maternal blood and its preliminary potential as a screening marker for preeclampsia.","authors":"Weiqiang Liu, Qin Lu, Weijie Xie, Liang Hu, Lijuan Wen, Shuxian Zeng, Jiatong Zhong, Nani Lin, Yanxiang Chen, Yimin Wang","doi":"10.1186/s10020-025-01307-1","DOIUrl":"10.1186/s10020-025-01307-1","url":null,"abstract":"","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"256"},"PeriodicalIF":6.0,"publicationDate":"2025-07-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12255149/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144619046","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Rhein alleviates hepatic steatosis in NAFLD mice by activating the AMPK/ACC/SREBP1 pathway to enhance lipid metabolism.","authors":"Weiwei Dai, Qishu Hou, Jifeng Ye","doi":"10.1186/s10020-025-01304-4","DOIUrl":"10.1186/s10020-025-01304-4","url":null,"abstract":"<p><strong>Background: </strong>Non-alcoholic fatty liver disease (NAFLD) is a common metabolic liver disorder characterized by excessive lipid accumulation. The 5'-adenosine monophosphate-activated protein kinase (AMPK)/acetyl-CoA carboxylase (ACC)/sterol regulatory element-binding protein 1 (SREBP1) pathway plays a pivotal role in regulating lipid metabolism. Rhein, a natural compound, has demonstrated hepatoprotective potential; however, its mechanism of action in NAFLD remains unclear. This study aimed to investigate whether rhein ameliorates NAFLD through modulation of the AMPK/ACC/SREBP1 pathway.</p><p><strong>Methods: </strong>A murine NAFLD model was established using a high-fat diet (HFD). Mice were treated with varying doses of rhein, and their body weight, liver, kidney, and retroperitoneal fat weights were recorded. Liver pathology was assessed by histological examination and Oil Red O staining. Serum lipid profiles, liver function biomarkers, and inflammatory cytokine levels were measured. Western blotting was employed to analyze the expression and phosphorylation of AMPK pathway-related proteins (AMPK, ACC, and SREBP1). To validate the involvement of this pathway, AMPK-IN-3 was intraperitoneally administered in combination with high-dose rhein to a subset of HFD-fed mice.</p><p><strong>Results: </strong>Rhein treatment significantly reduced body weight gain, organ weights, hepatic lipid accumulation, serum cholesterol and triglyceride levels, and the expression of inflammatory cytokines in NAFLD mice. It also improved liver function markers, enhanced AMPK phosphorylation, promoted ACC phosphorylation, and inhibited SREBP1 expression. Notably, co-treatment with AMPK-IN-3 attenuated these beneficial effects, confirming the mechanistic involvement of the AMPK/ACC/SREBP1 pathway.</p><p><strong>Conclusion: </strong>Rhein confers protective effects against HFD-induced NAFLD by activating the AMPK/ACC/SREBP1 signaling pathway, thereby enhancing hepatic lipid metabolism, reducing steatosis, and alleviating liver injury and inflammation. These findings suggest that rhein may serve as a promising therapeutic candidate for NAFLD.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"255"},"PeriodicalIF":6.0,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12247347/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144608775","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Validated metabolomic biomarkers in psychiatric disorders: a narrative review.","authors":"Marcela Konjevod, Jorge Sáiz, Lucía Bordoy, Dubravka Svob Strac, Ameer Y Taha, Senentxu Lanceros-Méndez, Rosa M Alonso","doi":"10.1186/s10020-025-01258-7","DOIUrl":"10.1186/s10020-025-01258-7","url":null,"abstract":"<p><p>Schizophrenia, major depressive disorder, bipolar disorder and posttraumatic stress disorder are severe and profoundly debilitating mental illnesses. Due to their heterogeneity and polygenic nature, the metabolic pathways and biological mechanisms underlying these conditions remain elusive. Consequently, diagnosing psychiatric disorders is a complex and multifaceted process, relying on clinical assessment and standardized diagnostic criteria. There is a growing demand to identify and integrate potential biomarkers for these disorders, especially for early diagnosis, to enhance diagnostic accuracy and complement existing diagnostic tools. Validating potential diagnostic biomarkers is essential to ensure their accuracy, reliability, generalizability, and clinical utility.In this article we provide a comprehensive review of validated metabolomics research, focusing on both the specific psychiatric conditions and the types of validation performed. Our scope is limited to peer-reviewed studies that include studies that performed validation studies in independent cohorts, cross-validation, or external validation. Due to the lack of published research, most of these validation studies have concentrated on major depressive disorder and schizophrenia, with fewer studies addressing bipolar disorder and posttraumatic stress disorder.Biomarkers are considered as validated if they demonstrated reproducibility in additional cohorts and biological relevance across independent datasets. However, several limitations must be acknowledged, including the heterogeneity in study design, small sample sizes, different analytical platforms, and inconsistent validation criteria across studies. Published results reveal that potential metabolomics biomarkers pertain to diverse categories pointing to a range of cellular, biological, and metabolic processes and emphasizing the intricate nature of psychiatric disorders. Such findings illustrate the formidable challenge of identifying and validating clinically useful metabolomic biomarkers and underscore the necessity for further research that encompasses various validation methodologies.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"254"},"PeriodicalIF":6.0,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12239260/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144601027","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting PFKFB3 to restore glucose metabolism in acute pancreatitis via nanovesicle delivery.","authors":"Hai Jiang, Zhipeng Xu, Qi Song, Junjie Tao, Jia Liu, Qiang Wang, Huaisheng Zhang, Heng Zhu, Qiliang Li, Lei Li","doi":"10.1186/s10020-025-01261-y","DOIUrl":"10.1186/s10020-025-01261-y","url":null,"abstract":"<p><strong>Background: </strong>Acute pancreatitis (AP) is a severe inflammatory disease frequently accompanied by disturbances in glucose metabolism, which further complicate the disease prognosis. This study aims to explore the role of PFKFB3, a key glycolytic enzyme, in regulating glucose metabolism in AP and assess the potential of PFKFB3 inhibition via nanovesicle delivery to mitigate metabolic dysfunction.</p><p><strong>Methods: </strong>Transcriptomic data from Gene Expression Omnibus (GEO), including single-cell RNA sequencing (scRNA-seq) and bulk RNA sequencing, were analyzed to investigate the molecular mechanisms involved in glucose metabolism dysregulation in AP. The therapeutic effects of PFKFB3 inhibition via nanovesicle-based delivery were evaluated using both in vivo and in vitro AP models.</p><p><strong>Results: </strong>PFKFB3 inhibition significantly restored normal glycolytic function and improved glucose metabolism in AP models. Moreover, nanovesicle-mediated delivery also alleviated both inflammation and metabolic disturbances, highlighting its promise as a therapeutic strategy for managing glucose dysfunction in AP.</p><p><strong>Conclusion: </strong>Our findings identify PFKFB3 as a critical therapeutic target for treating glucose metabolism disorders in acute pancreatitis. Nanovesicle-based PFKFB3 inhibition may serve as an innovative approach to address metabolic complications associated with AP, offering a new direction for therapeutic interventions in inflammatory diseases.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"253"},"PeriodicalIF":6.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229013/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567576","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tripartite motif 47 promotes the development of thyroid carcinoma through ADAR ubiquitination.","authors":"Hongzhou Liu, Xiaodong Hu, Tan Li, Yuhan Wang, Xiaomin Fu","doi":"10.1186/s10020-025-01298-z","DOIUrl":"10.1186/s10020-025-01298-z","url":null,"abstract":"<p><strong>Background: </strong>Tripartite motif 47 (TRIM47) plays a vital role in the carcinogenesis and drug resistance of various cancers, whereas the function of TRIM47 in thyroid carcinoma (TC) remains unclear.</p><p><strong>Methods: </strong>Human study and animal experiments were performed. Mass spectrometry, cellular invasion/metastasis assay, chemo-resistance assay, and ubiquitination evaluation were conducted to investigate the interaction between TRIM47 and adenosine deaminases acting on RNA (ADAR).</p><p><strong>Results: </strong>TRIM47 expression was increased in human tissues and cell lines of TC. Functional experiments demonstrated that TRIM47 expression enhanced malignant biological behaviors. With mass spectrometry, TRIM47 silencing could significantly decrease the chemo-resistance of TC cells to chemotherapeutic drugs. The interaction between TRIM47 and ADAR was mediated through the ubiquitin-proteasome pathway (UPP), which was approved by RNA interference procedure and co-immunoprecipitation.</p><p><strong>Conclusion: </strong>Comprehensively, glycogen synthase kinase-3β (GSK-3β)-associated ubiquitination is critical in the TRIM47-ADAR-GSK-3β axis. This study demonstrates that TRIM47 interacted with ADAR to facilitate ADAR protein degradation via ubiquitination and GSK-3β-associated phosphorylation, which serves as a novel therapeutic avenue for TC.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"252"},"PeriodicalIF":6.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12229022/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567577","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Reprogramming of liver metabolism during West Nile virus infection unveils novel aspects of disease pathophysiology.","authors":"Patricia Mingo-Casas, Ana-Belén Blázquez, Josefina Casas, Ana Esteban, Estela Escribano-Romero, Pedro J Sánchez-Cordón, Nereida Jiménez de Oya, Juan-Carlos Saiz, Miguel A Martín-Acebes","doi":"10.1186/s10020-025-01300-8","DOIUrl":"10.1186/s10020-025-01300-8","url":null,"abstract":"<p><strong>Background: </strong>West Nile virus (WNV) is a neurotropic mosquito-borne flavivirus responsible for outbreaks of encephalitis and meningitis worldwide. About 20% of infected patients exhibit abnormal liver function tests, although the participation of this organ in the pathophysiology of the disease remains unclear. To fill this gap, this study explores changes in liver metabolism during WNV infection.</p><p><strong>Methods: </strong>Given the relevance of the liver as a major immune and metabolic organ, the changes in response to WNV infection were analyzed in the mouse model combining transcriptomics, lipidomics and histopathological analyses.</p><p><strong>Results: </strong>Despite the absence of detectable viral replication in the liver, infection resulted in hepatic transcriptomic reprogramming that affected inflammation, immunity, biological oxidation and lipid metabolisms. Changes in the expression of genes related to glutathione metabolism, detoxification reactions, fatty acid metabolism (fatty acid oxidation and fatty acyl-CoA biosynthesis), phospholipid synthesis (phosphatidylcholine and phosphatidylethanolamine), sphingolipid synthesis, sterol metabolism and lipid droplet organization were identified. The reduction in glutathione in the liver of infected animals was confirmed and lipidomic analyses showed an increase in the content of sphingolipids, triacylglycerols and cholesteryl esters. A decrease in the cholesterol, phosphatidylcholine and phosphatidylethanolamine levels was also observed. Moreover, histopathological findings supported the development of steatosis in one-third of WNV-infected animals.</p><p><strong>Conclusions: </strong>The discovery of these underestimated metabolic aspects of the infection repurposes the impact of WNV on liver function. These results will contribute to a better understanding of the physiopathology of the disease and warrant special attention to liver function during WNV infection.</p>","PeriodicalId":18813,"journal":{"name":"Molecular Medicine","volume":"31 1","pages":"251"},"PeriodicalIF":6.0,"publicationDate":"2025-07-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12228371/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144567575","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}