Novel dual AMPK/NRF2 activation by leucocyanidin from Hawthorn (Crataegus) for mitochondria repair-Targeted therapy of hepatic steatosis

• A novel flavonoid, leucocyanidin, was identified from hawthorn as a promising therapeutic agent for MASLD. • Co-activation of the NRF2 and AMPK pathways was found to improve mitochondrial integrity and function, thereby restoring fatty acid β-oxidation. • Leucocyanidin serves as a small-molecule natural product that targets AMPK to regulate lipid metabolism. Background and purpose: Metabolic dysfunction-associated steatotic liver disease (MASLD) represents a global health challenge with limited therapeutic options. This study identified leucocyanidin (Leuc), a bioactive flavonoid from the traditional herb Crataegus pinnatifida (hawthorn), as a novel dual-target therapeutic agent against MASLD. Methods and results: We evaluated the effects of Leuc on a mouse model induced by a 60% high-fat diet and a cell model induced by free fatty acids (FFA). Compared to the model group, Leuc treatment dose-dependently significantly reduced liver weight, serum levels of TG and TC, hepatic inflammation markers (IL-6 and TNF-α), as well as cellular TG content. Histological and fluorescence analyses revealed a significant reduction in lipid droplet accumulation. Mechanistically, Leuc exerted its protective effects through two major pathways: (1) By activating the NRF2 antioxidant axis, Leuc attenuated oxidative stress-induced mitochondrial dysfunction and restored fatty acid β-oxidation capacity; (2) Through direct allosteric binding to AMPK, Leuc suppressed fatty acid uptake, inhibited lipogenesis, and enhanced mitochondrial fatty acid transport. Conclusion: These coordinated mechanisms reestablished hepatic lipid homeostasis, positioning Leuc as a promising dual-target natural compound for MASLD intervention through simultaneous AMPK/NRF2 activation.