Emodin Exerts Dual Hepatoprotective/Hepatotoxic Effects Dependent on Metabolic Microenvironment via Gut–Liver Axis Crosstalk: A Multi-Omics Study in MAFLD and Normal Mice

Emodin exhibits promising hepatomodulatory potential, yet its precise actions remain poorly characterized across distinct hepatic pathological states. Dose-dependent effects of emodin (40, 80, and 120 mg/kg) were investigated in mice with metabolic dysfunction-associated steatotic liver disease (MASLD), as well as healthy control mice, through integrated histopathological, biochemical, metabolomic, and gut microbiota profiling. The 80 mg/kg dose tended to yield the most favorable hepatoprotective outcomes in MASLD mice, whereas the 120 mg/kg dose was accompanied by apparent adverse hepatic alterations in normal mice. Correlative analyses further suggested that such divergent hepatic responses may be potentially linked to the gut microbiota–short-chain fatty acid (SCFA) axis, as well as the modulation of BAX/Bcl-2 balance and ESR1 expression. The hepatic effects of emodin are state- and dose-dependent. The dose of 80 mg/kg may represent a plausible candidate therapeutic range for MASLD, and the gut–liver axis is proposed as a likely underlying regulatory pathway.