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The workflow integrates two-sample Mendelian randomization using plasma proteomics and ALD GWAS, followed by functional enrichment and SMR-based control for genetic linkage confounding. Single-cell RNA sequencing in a murine ALD model determines hepatic cellular origins, and chronic-plus-binge ethanol feeding validates target roles in vivo, yielding four high-confidence proteins.",{"@graph":69,"@context":122},[70,84,105],{"@type":71,"itemListElement":72},"BreadcrumbList",[73,77,79,82],{"item":74,"name":75,"@type":76,"position":8},"https://docshare.wps.com","Home","ListItem",{"item":78,"name":9,"@type":76,"position":14},"https://docshare.wps.com/document/",{"item":80,"name":40,"@type":76,"position":81},"https://docshare.wps.com/document/research-report/",3,{"item":83,"name":65,"@type":76,"position":19},"https://docshare.wps.com/document/a-multiomics-approach-combining-causal-inference-and-in-vivo-validation-identifies-key-protein-drivers-of-alcohol-associated-liver-disease/437962/",{"url":83,"name":65,"@type":85,"image":86,"author":91,"headline":65,"publisher":94,"fileFormat":97,"inLanguage":63,"description":67,"dateModified":98,"datePublished":99,"encodingFormat":97,"isAccessibleForFree":100,"interactionStatistic":101},"DigitalDocument",{"url":87,"@type":88,"width":89,"height":90},"https://docshare.wps.com/thumbnails/a-multiomics-approach-combining-causal-inference-and-in-vivo-validation-identifies-key-protein-drivers-of-alcohol-associated-liver-disease/437962.png","ImageObject",300,407,{"name":92,"@type":93},"Rainbow Cat","Person",{"url":74,"name":95,"@type":96},"DocShare","Organization","application/pdf","2026-09-30","2026-09-29",true,{"@type":102,"interactionType":103,"userInteractionCount":8},"InteractionCounter",{"@type":104},"ViewAction",{"@type":106,"mainEntity":107},"FAQPage",[108,114,118],{"name":109,"@type":110,"acceptedAnswer":111},"What problem does the study aim to solve in alcohol-associated liver disease?","Question",{"text":112,"@type":113},"It targets the unresolved molecular mechanisms of ALD, especially the difficulty of separating correlational biomarkers from true causal disease drivers.","Answer",{"name":115,"@type":110,"acceptedAnswer":116},"Which main analytical framework was used to nominate causal proteins?",{"text":117,"@type":113},"A two-sample Mendelian randomization approach using large-scale plasma proteomics and ALD GWAS data, combined with functional enrichment and SMR validation.",{"name":119,"@type":110,"acceptedAnswer":120},"How were the causal protein targets validated in vivo and by which model?",{"text":121,"@type":113},"Their roles were phenocopied in a chronic-plus-binge ethanol feeding mouse model, where hepatic expression of specific risk and protective proteins shifted in direction consistent with disease pathogenesis.","https://schema.org",{"og:url":83,"og:type":124,"og:title":65,"og:site_name":95,"og:description":67},"article",{"robots":126,"canonical":83},"index,follow",{"doc_id":128,"site_id":62},437962,1790742851,{"code":4,"msg":5,"data":131},{"doc_id":128,"user_id":132,"nickname":92,"user_avatar":133,"doc_module":4,"category_id":39,"category_name":40,"doc_title":65,"doc_description":67,"doc_content":134,"file_id":135,"file_url":136,"file_type":137,"file_size":138,"view_count":8,"is_deleted":4,"is_public":8,"is_downloadable":8,"audit_status":8,"page_count":139,"language":140,"language_code":63,"site_id":62,"html_lang":63,"table_of_contents":141,"faqs":142,"seo_title":143,"seo_description":67,"update_tm":144,"read_time":145},962090769181,"https://ap-avatar.wpscdn.com/davatar_6f874abed73319feea01a86fa6f0fab8","TYPE Original Research PUBLISHED 05 December 2025 DOI 10.3389/fimmu.2025.1714502  \nOPEN ACCESS  \nEDITED BY  \nTheodoros Androutsakos,  \nNational and Kapodistrian University of Athens, Greece  \nREVIEWED BY  \nAntonios Chatzigeorgiou,  \nNational and Kapodistrian University of Athens, Greece  \nTanmoy Mondal,  \nHoward University, United States  \n*CORRESPONDENCE  \nXiaoli Wang  \n[wangjihuawangxiao@163.com](wangjihuawangxiao@163.com)[ ](wangjihuawangxiao@163.com)Liang Chu  \n [chew8151@163.com](chew8151@163.com)  \n†These authors have contributed equally to this work and share first authorship  \nRECEIVED 27 September 2025  \nREVISED 17 November 2025  \nACCEPTED 21 November 2025  \nPUBLISHED 05 December 2025  \nCORRECTED 22 December 2025  \nCITATION  \nZhou Q, Ma X, Cui Q, Zhang L, Yao C, Zhang Z, Wang X and Chu L (2025) A multiomics approach combining causal inference and in vivo validation identifies key protein drivers of alcohol-associated liver disease. Front. Immunol. 16:1714502 .  \ndoi: 10.3389/fimmu.2025.1714502  \nCOPYRIGHT  \n© 2025 Zhou, Ma, Cui, Zhang, Yao, Zhang, Wang and Chu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY) . The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.  \nA multi-omics approach combining causal inference and in vivo validation identifies key protein drivers of alcoholassociated liver disease  \nQingyi Zhou 1,2,3†, Xuan Ma 4†, Qianqian Cui 2, Lei Zhang 1, Chao Yao 1, Zilu Zhang 2, Xiaoli Wang 3,5* and Liang Chu 1*  \n1Second Affiliated Hospital of Bengbu Medical University, Bengbu, China, 2 Bengbu Medical University, Bengbu, China, 3Anhui Key Laboratory of Infection and Immunity of Bengbu Medical College, Bengbu, China, 4School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China, 5 Department of Basic Medical College, Bengbu Medical University, Bengbu, China  \nBackground: Alcohol-associated liver disease (ALD) constitutes a global health crisis, yet the molecular mechanisms driving its pathogenesis remain unresolved, critically impeding the development of effective therapeutics. A fundamental challenge is the differentiation of correlational biomarkers from the causal drivers of disease. Here, we perform a systematic characterization of the ALD causal proteo me to uncover novel pathogenic mediator s and prioritize therapeutic targets.  \nMethods: We implemented a multi-stage pipeline integrating human genetics with multi-level experimental validation. A two-sample Mendelian randomization (MR) framework, leveraging large-scale plasma proteomics and ALD GWAS data, was employed to nominate proteins causally linked to ALD. These candidates underwent functional enrichment analysis to delineate their biological roles. To rigorously control for confounding by genetic linkage, findings were validated using SMR. We then employed single-cell RNA sequencing from a murine ALD model to determine the hepatic cellular origins of the validated targets. Finally, their functional relevance was established in vivo using a chronic-plus-binge ethanol feeding mouse model.  \nResults: Our MR analysis identified 17 proteins with a putative causal association with ALD. Functional enrichment analysis implicated these candidates in inflammatory and immune response pathways. After stringent SMR validation, we identified four high-confidence causal proteins: TREML2 (Triggering Receptor Expressed on Myeloid cells-like 2) and MM P12 (Matrix Metallopeptidase 12) as risk factors, and PLA2R1 (Phospholipase A2 Receptor 1) and MAX (MYC Associated Factor X) as protective factors. Single-cell transcriptomics resolved the cellular sources of these proteins within the liver, identifying hepa","cbCaifIT5JJh6oW5","https://ap.wps.com/l/cbCaifIT5JJh6oW5","pdf",8146461,15,"English","# Background\n# Methods\n# Results\n# Conclusion\n# Keywords\n# Introduction","[{\"question\":\"What problem does the study aim to solve in alcohol-associated liver disease?\",\"answer\":\"It targets the unresolved molecular mechanisms of ALD, especially the difficulty of separating correlational biomarkers from true causal disease drivers.\"},{\"question\":\"Which main analytical framework was used to nominate causal proteins?\",\"answer\":\"A two-sample Mendelian randomization approach using large-scale plasma proteomics and ALD GWAS data, combined with functional enrichment and SMR validation.\"},{\"question\":\"How were the causal protein targets validated in vivo and by which model?\",\"answer\":\"Their roles were phenocopied in a chronic-plus-binge ethanol feeding mouse model, where hepatic expression of specific risk and protective proteins shifted in direction consistent with disease pathogenesis.\"}]","A multiomics approach combining causal inference and in vivo validation identifies key protein drivers of alcohol-associated liver disease | PDF",1790683658,38]