Glabranin counteracts MAFLD by stimulating liver lipid catabolism via the PKA-AMPK axis

Abstract Background: Metabolic dysfunction-associated fatty liver disease (MAFLD) is the most prevalent chronic liver disorder worldwide and remains without effective pharmacological interventions capable of targeting the underlying metabolic dysfunction. Here, we investigated the therapeutic potential and molecular mechanisms of action of glabranin, a prenylated flavanone isolated from Glycyrrhiza glabra leaves, in complementary in vitro and in vivo models of steatosis. Methods: Steatosis was induced in HepG2 cells by exposure to oleic and palmitic acids, and in Drosophila melanogaster through high-fat diet feeding. The effects of glabranin on lipid droplets accumulation and metabolic homeostasis were evaluated using integrated phenotypic, proteomic, and kinome analyses. Results: Glabranin markedly reduced intracellular lipid droplets accumulation in oleic/palmitic acid-overloaded HepG2 cells, as well as in Huh7 cells. Integrated proteomic and kinome profiling revealed robust activation of the cAMP-PKA-AMPK signaling axis, accompanied by coordinated induction of lipid-catabolic pathways. Mechanistically, glabranin enhanced lipolysis and lipophagy, promoted mitochondrial β-oxidation, and stimulated NRF2-dependent antioxidant responses, thereby restoring metabolic flexibility and reducing lipotoxic stress. The metabolic benefits of glabranin were confirmed in vivo using a high-fat diet-induced D. melanogaster model. Glabranin supplementation significantly decreased lipid accumulation, restored locomotor performance, and improved survival, demonstrating efficacy across evolutionarily conserved metabolic pathways. Conclusions: Our findings identify glabranin as a previously unrecognized metabolic modulator that reprograms hepatic lipid metabolism through activation of the cAMP-PKA-AMPK network. By simultaneously enhancing lipid droplets clearance, mitochondrial fatty acid utilization, and antioxidant defense, glabranin effectively counteracts steatotic state in both in vitro and in vivo models. These results position glabranin as a promising candidate for the prevention and treatment of early-stage MAFLD and provide a strong rationale for its further preclinical development.