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This study aimed to define MgIG\u2019s hepatoprotective actions in chronic-binge ALD mouse models and ethanol\/palmitic acid-exposed AML-12 hepatocytes. Through an integrated strategy encompassing RNA sequencing, molecular docking, and microscale thermophoresis, we discovered that MgIG directly binds to hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) at residue 187, a finding corroborated by molecular dynamics simulations. In vivo, MgIG markedly attenuated alcohol-induced liver injury, evidenced by ameliorated histological damage, reduced hepatic steatosis, and normalized liver-to-body weight ratios. In vitro, it effectively reduced lipid accumulation, inflammation, and apoptosis. Mechanistically, RNA sequencing identified isopentenyl diphosphate delta isomerase 1 (IDI1) as a key downstream effector. Hepatocyte-specific genetic manipulations confirmed that MgIG modulates the SREBP2\u2013IDI1 axis, thereby suppressing lipogenesis, inflammatory responses, and apoptotic pathways. We reveal HSD11B1 as a novel direct molecular target of MgIG and elucidate its therapeutic mechanism through the HSD11B1\u2013SREBP2\u2013IDI1 signaling axis, which profoundly impacts ALD pathogenesis. These findings not only validate MgIG\u2019s clinical utility but also highlight a promising new therapeutic target for ALD.<\/jats:p>","DOI":"10.7554\/elife.109174","type":"journal-article","created":{"date-parts":[[2026,2,6]],"date-time":"2026-02-06T14:30:44Z","timestamp":1770388244000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.109174","source":"Crossref","is-referenced-by-count":0,"title":["Magnesium isoglycyrrhizinate alleviates alcohol-associated liver disease through targeting HSD11B1"],"prefix":"10.7554","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1601-2068","authenticated-orcid":true,"given":"Lu","family":"Xiao","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/05d5vvz89","id-type":"ROR","asserted-by":"publisher"}],"name":"Clinical Medicine Research Institute and Department of Anesthesiology, The First Affiliated Hospital of Jinan University","place":["Guangzhou, China"]},{"name":"Department of Gastroenterology, People\u2019s 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