Dietary Citrus Flavonoid Hesperetin Attenuates Metabolic Dysfunction–Associated Steatotic Liver Disease via Modulation of MAPK–RARα Axis

Abstract Metabolic dysfunction–associated steatotic liver disease (MASLD) lacks effective nutrition-based interventions. Hesperetin, a dietary citrus flavonoid, was evaluated for its hepatoprotective mechanism using high-fat diet–induced MASLD mice and free fatty acid–challenged hepatocytes. Hesperetin improved glucose and lipid metabolism, alleviated steatosis and inflammation, and restored hepatic function. Integrated transcriptomics and network analysis indicated activation of retinol metabolism and inhibition of MAPK signaling. Mechanistic studies showed that hesperetin suppressed aberrant MAPK activity, preserved retinoic acid receptor α (RARα) function, upregulated RARα-dependent metabolic genes, and reduced lipogenic gene expression. Pharmacological blockade or siRNA knockdown of RARα abrogated hesperetin’s lipid-lowering effects, confirming RARα as an essential mediator. These findings identify hesperetin as a food-derived modulator of the MAPK–RARα axis that restores retinoid signaling and ameliorates hepatic lipid dysregulation, highlighting its potential as a targeted nutritional strategy for MASLD management.