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Growing evidence indicates that MASLD is a systemic disease in which epigenetic changes\u2014including DNA and RNA methylation as well as histone modifications\u2014drive its progression by integrating metabolic and inflammatory signals across organs. This review introduces the concept of \u201cnetworked epigenome cascades\u201d and highlights how epigenetic alterations in extrahepatic metabolic organs contribute to insulin resistance (IR) and systemic inflammation. MASLD is thereby reframed as a disorder of systemic epigenomic miscommunication rather than a liver\u2010only disease. We further discuss preclinical and emerging interventions, with an emphasis on natural compounds that modulate epigenomic regulation, while noting the uncertainties that remain regarding their translational potential for MASLD. By positioning the epigenome as a central mechanism, this review underscores its promise for biomarker development and mechanistically targeted interventions, although robust validation in humans is still required.<\/jats:p>","DOI":"10.1111\/obr.70219","type":"journal-article","created":{"date-parts":[[2026,9,1]],"date-time":"2026-09-01T01:40:40Z","timestamp":1788226840000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Epigenomic Cascades Across Organs in Metabolic Dysfunction\u2013Associated Steatotic Liver Disease: New Therapeutic Horizons"],"prefix":"10.1111","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-8805-8384","authenticated-orcid":false,"given":"Shurui","family":"Yang","sequence":"first","affiliation":[{"name":"Acupuncture and Moxibustion Department, Hubei Provincial Hospital of Traditional Chinese Medicine Affiliated Hospital of Hubei University of Chinese Medicine  Wuhan China"},{"name":"College 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