{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,28]],"date-time":"2026-10-28T18:04:35Z","timestamp":1793210675475,"version":"4.5.0"},"reference-count":29,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T00:00:00Z","timestamp":1759276800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Metabolic-associated fatty liver disease (MAFLD) is a leading cause of chronic liver disease and is closely linked to type 2 diabetes mellitus (T2DM). The pathogenesis of MAFLD involves complex metabolic imbalances, including impaired fatty acid \u03b2-oxidation and chronic inflammation. GLP-1 receptor agonists (GLP-1 RAs) have shown promise in improving metabolic outcomes, but their specific effects on MAFLD remain unclear. This study aims to investigate the molecular mechanisms underlying the hepatic benefits of semaglutide, a GLP-1 RA, in T2DM patients with MAFLD using serum proteomics and metabolomics.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We conducted a single-centre, longitudinal, data-driven study involving 75 T2DM patients with MAFLD (pre-treatment, PT) and 100 healthy controls (health control, HC). Patients received semaglutide treatment (0.25 mg\/week initially, escalated to 0.5 mg\/week) for 12 weeks. Serum proteomic and metabolomic profiles were analyzed using 4D-DIA proteomics and LC-MS before and after treatment. Biomarker discovery involved the identification of differential metabolites and proteins, pathway analysis, and integration of proteomic and metabolomic data. Clinical and biochemical parameters were also assessed.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>Semaglutide significantly improved metabolic and liver parameters, including HbA1c, BMI, HOMA-IR, liver function, IL-6, and liver stiffness (p &amp;lt; 0.01). Multivariate analysis revealed distinct proteomic and metabolomic profiles between baseline and post-treatment groups. A total of 203 differential metabolites and 61 proteins were identified, with key changes including reductions in long-chain fatty acids and inflammatory mediators, alongside increases in carnitine derivatives and anti-inflammatory proteins. Pathway analysis highlighted effects on fatty acid metabolism, PPAR signaling, and NAFLD-related pathways.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>Our study provides a comprehensive multi-omics analysis revealing that semaglutide modulates serum proteomic and metabolomic profiles in T2DM-MAFLD patients, potentially through enhancing mitochondrial \u03b2-oxidation, reducing lipid toxicity, and suppressing inflammation. These findings offer mechanistic insights into the hepatic benefits of semaglutide and support its potential as a therapeutic agent for MAFLD. This innovative approach advances our understanding of GLP-1 RAs\u2019 multi-organ protective effects and provides a foundation for developing precision medicine strategies for MAFLD.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fendo.2025.1650729","type":"journal-article","created":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T05:51:21Z","timestamp":1759297881000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Multi-omics analysis of hepatic outcomes in T2DM-MAFLD patients treated with semaglutide: a single-centre, longitudinal, data-driven study"],"prefix":"10.3389","volume":"16","author":[{"given":"Shu","family":"Niu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuchun","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Di","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenxi","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianchao","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiantong","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yubin","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,10,1]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1999","DOI":"10.1053\/j.gastro.2019.11.312","article-title":"MAFLD: A consensus-driven proposed nomenclature for metabolic associated fatty liver disease","volume":"158","author":"Eslam","year":"2020","journal-title":"Gastroenterology"},{"key":"B2","doi-asserted-by":"publisher","first-page":"73","DOI":"10.1002\/hep.28431","article-title":"Global epidemiology of nonalcoholic fatty liver disease-Meta-analytic assessment of prevalence, incidence, and outcomes","volume":"64","author":"Younossi","year":"2016","journal-title":"Hepatology"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.2337\/dc17-1902","article-title":"Nonalcoholic fatty liver disease and risk of incident type 2 diabetes: A meta-analysis","volume":"41","author":"Mantovani","year":"2018","journal-title":"Diabetes Care"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1038\/s41591-018-0104-9","article-title":"Mechanisms of NAFLD development and therapeutic strategies","volume":"24","author":"Friedman","year":"2018","journal-title":"Nat Med"},{"key":"B5","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1038\/s41575-021-00448-y","article-title":"The complex link between NAFLD and type 2 diabetes mellitus - mechanisms and treatments","volume":"18","author":"Targher","year":"2021","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1136\/gutjnl-2017-313884","article-title":"Non-alcoholic fatty liver disease and its relationship with cardiovascular disease and other extrahepatic diseases","volume":"66","author":"Adams","year":"2017","journal-title":"Gut"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s10620-016-4054-0","article-title":"Role of dietary fructose and hepatic de novo lipogenesis in fatty liver disease","volume":"61","author":"Softic","year":"2016","journal-title":"Dig Dis Sci"},{"key":"B8","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/nrgastro.2016.147","article-title":"NAFLD and diabetes mellitus","volume":"14","author":"Tilg","year":"2017","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(15)00803-X","article-title":"Liraglutide safety and efficacy in patients with non-alcoholic steatohepatitis (LEAN): a multicentre, double-blind, randomised, placebo-controlled phase 2 study","volume":"387","author":"Armstrong","year":"2016","journal-title":"Lancet"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1161\/ATVBAHA.115.305447","article-title":"GLP-1 receptor agonist exenatide increases capillary perfusion independent of nitric oxide in healthy overweight men","volume":"35","author":"Smits","year":"2015","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1002\/phar.70005","article-title":"The potential role of GLP-1 receptor agonists in osteoarthritis","volume":"45","author":"Ryan","year":"2025","journal-title":"Pharmacotherapy"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.2106\/JBJS.24.00468","article-title":"Glucagon-like peptide-1 receptor agonists decrease medical and surgical complications in morbidly obese patients undergoing primary TKA","volume":"107","author":"Kim","year":"2025","journal-title":"J Bone Joint Surg Am"},{"key":"B13","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1016\/j.cld.2017.08.002","article-title":"The genetics of pediatric nonalcoholic fatty liver disease","volume":"22","author":"Goyal","year":"2018","journal-title":"Clin Liver Dis"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/nrm.2016.25","article-title":"Metabolomics: beyond biomarkers and towards mechanisms","volume":"17","author":"Johnson","year":"2016","journal-title":"Nat Rev Mol Cell Biol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/nature19949","article-title":"Mass-spectrometric exploration of proteome structure and function","volume":"537","author":"Aebersold","year":"2016","journal-title":"Nature"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1007\/s11306-007-0082-2","article-title":"Proposed minimum reporting standards for chemical analysis Chemical Analysis Working Group (CAWG) Metabolomics Standards Initiative (MSI)","volume":"3","author":"Sumner","year":"2007","journal-title":"Metabolomics"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth1019","article-title":"Target-decoy search strategy for increased confidence in large-scale protein identifications by mass spectrometry","volume":"4","author":"Elias","year":"2007","journal-title":"Nat Methods"},{"key":"B18","doi-asserted-by":"publisher","first-page":"289","DOI":"10.1111\/j.2517-6161.1995.tb02031.x","article-title":"Controlling the false discovery rate: A practical and powerful approach to multiple testing","volume":"57","author":"Benjamini","year":"2018","journal-title":"J R Stat Soc: Ser B (Methodol)"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1002\/hep.23229","article-title":"The plasma lipidomic signature of nonalcoholic steatohepatitis","volume":"50","author":"Puri","year":"2009","journal-title":"Hepatology"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1111\/dom.12973","article-title":"Non-alcoholic fatty liver disease (NAFLD) prevalence and its metabolic associations in patients with type 1 diabetes and type 2 diabetes","volume":"19","author":"Cusi","year":"2017","journal-title":"Diabetes Obes Metab"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1007\/BF03261931","article-title":"Carnitine and acylcarnitines: pharmacokinetic, pharmacological and clinical aspects","volume":"51","author":"Reuter","year":"2012","journal-title":"Clin Pharmacokinet"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/j.jhep.2006.11.019","article-title":"The Interleukin-1 receptor antagonist is a direct target gene of PPARalpha in liver","volume":"46","author":"Stienstra","year":"2007","journal-title":"J Hepatol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1038\/s41575-018-0009-6","article-title":"Triggering and resolution of inflammation in NASH","volume":"15","author":"Schuster","year":"2018","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202306871","article-title":"SRSF1 is required for mitochondrial homeostasis and thermogenic functi on in brown adipocytes through its control of ndufs3 splicing","volume":"11","author":"Yuan","year":"","journal-title":"Adv Sci"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1016\/j.cmet.2009.02.002","article-title":"A branched-chain amino acid-related metabolic signature that differentiates obese and lean humans and contributes to insulin resistance","volume":"9","author":"Newgard","year":"2009","journal-title":"Cell Metab"},{"key":"B26","doi-asserted-by":"publisher","first-page":"108618","DOI":"10.1016\/j.jnutbio.2021.108618","article-title":"Dietary cocoa ameliorates non-alcoholic fatty liver disease and increa ses markers of antioxidant response and mitochondrial biogenesis in hi gh fat-fed mice","volume":"92","author":"Sun","year":"2021","journal-title":"J Nutr Biochem"},{"key":"B27","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.jnutbio.2021.108618","article-title":"Protective and therapeutic effects of fucoxanthin against sunburn caus ed by UV irradiation","volume":"132","author":"Matsui","year":"2016","journal-title":"J Pharmacol Sci"},{"key":"B28","doi-asserted-by":"publisher","first-page":"109709","DOI":"10.1016\/j.isci.2024.109709","article-title":"Hepatokine ITIH3 protects against hepatic steatosis by downregulating mitochondrial bioenergetics and de novo lipogenesis","volume":"27","author":"Talari","year":"2024","journal-title":"iScience"},{"key":"B29","doi-asserted-by":"publisher","first-page":"23","DOI":"10.1146\/annurev-physiol-021115-105045","article-title":"The biochemistry and physiology of mitochondrial fatty acid \u03b2-oxidation and its genetic disorders","volume":"78","author":"Houten","year":"2016","journal-title":"Annu Rev Physiol"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1650729\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,1]],"date-time":"2025-10-01T05:51:23Z","timestamp":1759297883000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2025.1650729\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,1]]},"references-count":29,"alternative-id":["10.3389\/fendo.2025.1650729"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2025.1650729","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,1]]},"article-number":"1650729"}}