Magnesium isoglycyrrhizinate alleviates alcohol-associated liver disease through targeting HSD11B1

While magnesium isoglycyrrhizinate (MgIG) is a clinically approved therapy for alcohol-associated liver disease (ALD), its precise molecular targets and mechanisms remain uncharacterized. This study aimed to define MgIG's hepatoprotective actions in chronic-binge ALD mouse models and ethanol/palmitic acid-exposed AML-12 hepatocytes. We employed an integrated approach combining RNA sequencing, molecular docking, microscale thermophoresis, and molecular dynamics simulations to investigate the molecular targets of magnesium isoglycyrrhizinate (MgIG). Chronic-binge alcohol-fed mouse models and ethanol/palmitic acid-exposed AML-12 hepatocytes were used to evaluate its hepatoprotective effects. Hepatocyte-specific genetic manipulations were performed to validate downstream signaling pathways. MgIG was found to directly bind hydroxysteroid 11-beta dehydrogenase 1 (HSD11B1) at residue Lys187. In vivo, MgIG significantly ameliorated alcohol-induced liver injury, reducing histological damage, hepatic steatosis, and abnormal liver-to-body weight ratios. In vitro, it attenuated lipid accumulation, inflammatory responses, and apoptosis. Transcriptomic analysis identified isopentenyl diphosphate delta isomerase 1 (IDI1) as a key downstream effector, and genetic validation confirmed that MgIG modulates the HSD11B1-SREBP2-IDI1 axis, thereby suppressing lipogenesis, inflammation, and apoptosis. We reveal HSD11B1 as a novel direct molecular target of MgIG and elucidate its therapeutic mechanism through the HSD11B1-SREBP2-IDI1 signaling axis, which profoundly impacts ALD pathogenesis.