Baicalin improves metabolic dysfunction-related fatty liver disease in mice by regulating the AMPK/mTOR/SREBP-1 signaling axis

Background Metabolic dysfunction-associated fatty liver disease (MASLD) is now a prevalent chronic liver disease, yet broadly applicable drug therapies remain limited. Baicalin exhibits antioxidant and anti-inflammatory activities; however, how baicalin ameliorates MASLD remains unclear. This study therefore assessed its therapeutic effects and related signaling pathways in a high-fat diet–induced mouse model of MASLD. Methods MASLD was established in C57BL/6 mice through continuous feeding with a high-fat diet. At the 8th week, the animals were randomized into five groups: a normal control, a disease model, and three baicalin-treated cohorts receiving 50, 100, or 200 mg/kg of the compound via daily oral gavage over a 4-week period. Serum biochemistry, liver histopathology (using H&E, Oil Red O, and Masson), inflammatory cytokines (ELISA), and oxidative stress markers were assessed. Molecular docking was performed to predict the potential binding mode between baicalin and AMPK. Western blotting detected pathway- and autophagy-related proteins. DNA fragmentation was assessed by TUNEL assay, and the numbers of autophagosomes and autolysosomes were observed under a transmission electron microscope. Results Model mice showed significant elevations in serum ALT, AST, TG, and TC. Liver tissue exhibited marked steatosis, inflammatory infiltration, and collagen deposition. Proinflammatory cytokines rose, while SOD and GSH fell and MDA rose. The aforementioned indices in the baicalin-treated groups showed varying degrees of improvement. Docking predicted a binding energy of −9.317 kcal/mol between baicalin and AMPK. Baicalin activated AMPK (higher p-AMPK/AMPK), suppressed mTOR (lower p-mTOR/mTOR) and SREBP-1/ACC/FAS, upregulated SIRT1/LKB1/PGC-1α, and increased LC3-II, Beclin-1, and ATG5, and decreased p62 were accompanied by increased autophagosome and autolysosome numbers. Conclusion Baicalin improves MASLD in mice by regulating the AMPK/mTOR/SREBP-1 axis, reducing oxidative stress and inflammation, and modulating the expression of autophagy-related markers. However, its direct molecular target and its effect on autophagic flux remain to be further validated.