{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:49:42Z","timestamp":1787028582111,"version":"build-2736575974"},"reference-count":60,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T00:00:00Z","timestamp":1777334400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasingly recognized as a systemic disorder shaped by genetic variants and network-level interactions beyond obesity and insulin resistance. This study aimed to define the genetic and proteomic architecture of MASLD by integrating GWAS and plasma proteomic profiling from the UK Biobank. Genome-wide association analyses were conducted under additive and dominant models, with functional annotations performed using SIFT, PolyPhen-2, PROVEAN, REVEL, CADD, MutationTaster, and conservation metrics (GERP++, phyloP, phastCons, and B-statistic). Differential protein expression was assessed using the Olink\u00ae platform, and STRING was applied for protein\u2013protein interaction analysis. MASLD patients showed male predominance and significant differences in hepatic (AST, ALT, GGT, PDFF), metabolic (glucose, triglycerides, TyG index), and inflammatory markers (CRP, neutrophils, NLR, CAR). GWAS confirmed PNPLA3 (rs738409, I148M) and TM6SF2 (rs58542926, E167K) as major risk variants, while SAMM50 and NCAN showed weaker but conserved associations. Proteomics revealed downregulation of IGFBP2, IGFBP1, PON3, CKB, and APOF and upregulation of CPM, IGSF9, GUSB, ACY1, AFM, LEP, and GSTA1\/3. PPI analysis identified ADIPOQ, LEP, FGF21, and ADH1B as central hubs in metabolic and inflammatory regulation. MASLD should be regarded as a network disease involving lipid metabolism, insulin\/IGF signaling, mitochondrial function, and ECM\u2013inflammatory pathways. These findings highlight PNPLA3 and TM6SF2 as major genetic drivers, while SAMM50, NCAN, and peripheral proteins contribute regulatory roles, suggesting novel biomarkers and therapeutic targets.<\/jats:p>","DOI":"10.3390\/ijms27093920","type":"journal-article","created":{"date-parts":[[2026,4,28]],"date-time":"2026-04-28T11:33:37Z","timestamp":1777376017000},"page":"3920","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["UK Biobank-Based Genetic and Proteomic Network Insights into Metabolic Dysfunction-Associated Steatotic Liver Disease Pathogenesis"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0358-2304","authenticated-orcid":false,"given":"Sang Wook","family":"Kang","sequence":"first","affiliation":[{"name":"Department of Oral and Maxillofacial Pathology, College of Dentistry, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Su Kang","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Laboratory Science, Catholic Kwandong University, Gangneung 25601, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1992-5188","authenticated-orcid":false,"given":"Ju Yeon","family":"Ban","sequence":"additional","affiliation":[{"name":"Department of Dental Pharmacology, College of Dentistry, Dankook University, Cheonan 31116, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Min Su","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Surgery, School of Medicine, Kyung Hee University, Seoul 02447, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,4,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"E8","DOI":"10.1097\/HEP.0000000000000966","article-title":"Letter to the Editor: A multi-society Delphi consensus statement on new fatty liver disease nomenclature","volume":"81","author":"Alswat","year":"2025","journal-title":"Hepatology"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.jhep.2020.01.013","article-title":"NAFLD as a driver of chronic kidney disease","volume":"72","author":"Byrne","year":"2020","journal-title":"J. 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