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This review summarizes recent advances in understanding the genetic architecture of MASLD. Genome-wide association studies (GWAS) have identified several key risk variants, primarily in genes such as PNPLA3, TM6SF2, GCKR, and MBOAT7, which influence hepatic lipid metabolism and disease progression. By utilizing surrogate markers of MASLD, researchers have also identified numerous putative MASLD-associated genes, warranting further investigation through functional genomics approaches. Next-generation sequencing techniques have uncovered rare variants in genes like APOB and ABCB4, as well as protective variants in HSD17B13 and CIDEB. This review discusses the potential of polygenic risk scores for disease stratification and the development of genetically informed therapeutic strategies. Additionally, it explores the future of functional genomics approaches in discovering novel treatment strategies. While the evolving genetic landscape of MASLD provides promising insights for precision medicine approaches in diagnosis, prognosis, and treatment, significant translational gaps remain. Addressing these challenges will be critical for realizing the full potential of personalised approaches in clinical management. This review synthesizes these findings and discusses their implications for future research and clinical practice in MASLD.<\/jats:p>","DOI":"10.3390\/ijms262210881","type":"journal-article","created":{"date-parts":[[2025,11,10]],"date-time":"2025-11-10T08:57:55Z","timestamp":1762765075000},"page":"10881","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Genomic Signatures of MASLD: How Genomics Is Redefining Our Understanding of Metabolic Liver Disease"],"prefix":"10.3390","volume":"26","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7807-9009","authenticated-orcid":false,"given":"Peter","family":"Saliba-Gustafsson","sequence":"first","affiliation":[{"name":"Cardio Metabolic Unit, Department of Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden"},{"name":"Medicine Unit of Endocrinology, Theme Inflammation and Ageing, Karolinska University Hospital C2:94, 141 86 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6190-7365","authenticated-orcid":false,"given":"Jennifer","family":"H\u00e4rdfeldt","sequence":"additional","affiliation":[{"name":"Cardio Metabolic Unit, Department of Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden"},{"name":"Medicine Unit of Endocrinology, Theme Inflammation and Ageing, Karolinska University Hospital C2:94, 141 86 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0771-0569","authenticated-orcid":false,"given":"Matteo","family":"Pedrelli","sequence":"additional","affiliation":[{"name":"Cardio Metabolic Unit, Department of Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden"},{"name":"Cardio Metabolic Unit, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6541-8542","authenticated-orcid":false,"given":"Paolo","family":"Parini","sequence":"additional","affiliation":[{"name":"Cardio Metabolic Unit, Department of Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden"},{"name":"Medicine Unit of Endocrinology, Theme Inflammation and Ageing, Karolinska University Hospital C2:94, 141 86 Stockholm, Sweden"},{"name":"Cardio Metabolic Unit, Department of Laboratory Medicine, Karolinska Institutet, 171 77 Stockholm, Sweden"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"European Association for the Study of the Liver (EASL), European Association for the Study of Diabetes (EASD), and European Association for the Study of Obesity (EASO) (2016). 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