肝臓標的エピカテキンナノ粒子はオートファジーを促進し、代謝機能障害関連脂肪肝疾患におけるミトコンドリア機能を強化する

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.

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.

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.

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.