BACKGROUND: Myricetin, a bioactive flavonoid from Abelmoschus manihot, has demonstrated therapeutic potential for metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive form, metabolic dysfunction-associated steatohepatitis (MASH). However, its precise mechanisms, particularly concerning mitochondrial homeostasis, remain inadequately elucidated.
OBJECTIVES: The present study evaluated the therapeutic efficacy of myricetin in alleviating hepatic steatosis, inflammation, fibrosis, and insulin resistance associated with MASLD/MASH, with a specific focus on unraveling the role of mitophagy regulation.
METHODS: MASLD and MASH models were established in mice using a high-fat diet (HFD) or a Gubra-Amylin NASH (GAN) diet, followed by myricetin treatment. Systemic metabolism, liver injury, histology, and insulin sensitivity were assessed. Transcriptomic profiling was performed to analyze metabolic pathways. Molecular docking, surface plasmon resonance (SPR), co-immunoprecipitation, and immunofluorescence were used to study the interaction between myricetin and PINK1 and its impact on PINK1/Parkin-mediated mitophagy. Finally, in vitro loss-of-function experiments using shPINK1 were conducted to validate the mechanism.
RESULTS: Myricetin significantly ameliorated hepatic steatosis, inflammation, fibrosis, and systemic insulin resistance in MASLD/MASH mice. Transcriptomics revealed enhanced fatty acid β-oxidation and mitochondrial function. Mechanistically, myricetin directly bound to PINK1, inhibiting its mitochondrial import through the TOM complex (TOM40) and subsequent cleavage by the PARL protease, thereby stabilizing PINK1 on the outer mitochondrial membrane. This stabilization activated PINK1/Parkin-dependent mitophagy, restoring mitochondrial integrity. Notably, the myricetin-mediated improvements in mitophagy and mitochondrial function were negated by PINK1 silencing.
CONCLUSION: Myricetin mitigates MASLD/MASH progression by acting as a novel PINK1 stabilizer, augmenting PINK1/Parkin-dependent mitophagy to enhance mitochondrial quality. This study highlights myricetin as a potent intervention targeting mitochondria to combat metabolic liver diseases.
