Hepatocyte-Targeted Epicatechin Nanoparticles Promote Autophagy and Enhance Mitochondrial Function in Metabolic Dysfunction-Associated Steatotic Liver Disease.

Introduction: Metabolic dysfunction-associated steatotic liver disease has limited treatment options, posing a serious global health challenge. Epicatechin (EC), a natural flavonoid, exhibits therapeutic potential; however, its clinical utility is hindered by its low solubility and limited bioavailability. Therefore, in this study, we developed liver-targeted EC-loaded galactosylated poly(lactic-co-glycolic acid)-polyethylene glycol nanoparticles (EC@PLGA-PEG-GAL NPs) with high therapeutic efficacy. Methods: EC@PLGA-PEG-GAL NPs were synthesized, and their physicochemical properties, biocompatibility, and hepatocyte-targeted cellular uptake were characterized. The therapeutic efficacy of the NPs was assessed in high-fat diet (HFD)-fed mice, evaluating metabolic dysfunction and hepatic steatosis. Mechanistic studies were performed to investigate the effects on autophagic flux and mitochondrial function. Results: The EC@PLGA-PEG-GAL NPs exhibited improved EC solubility, sustained drug release, and low cytotoxicity. In HFD-fed mice, administration of EC@PLGA-PEG-GAL NPs significantly ameliorated hepatic steatosis, reduced insulin resistance, and alleviated metabolic dysfunction, without causing toxicity. Mechanistically, these NPs restored the autophagic flux by activating the AMP-activated protein kinase pathway and inhibiting mechanistic target of rapamycin complex 1 signaling, thereby enhancing ubiquitinated protein clearance. They also alleviated mitochondrial dysfunction by enhancing the membrane potential, reducing the reactive oxygen species levels, and promoting mitochondrial biogenesis. Conclusion: Our findings highlight EC@PLGA-PEG-GAL NPs as promising liver-targeted nanotherapeutics simultaneously modulating autophagy and mitochondrial functions in metabolic dysfunction-associated steatotic liver disease.