Metformin Alleviates Liver Metabolic Dysfunction in Polycystic Ovary Syndrome by Activating the Ethe1/Keap1/PINK1 Pathway

Background: Polycystic ovary syndrome (PCOS) is a reproductive endocrine disease characterized by metabolic abnormalities, with 34-70% of patients with PCOS also presenting non-alcoholic fatty liver disease (NAFLD). Metformin is a first-line treatment for relieving insulin resistance in PCOS; however, the potential therapeutic application of metformin for preventing NAFLD/metabolic dysfunction-associated fatty liver disease (MAFLD) in PCOS remains under-explored. Here, we investigated the potential protective effects and the underlying mechanisms of metformin against hepatic lipid metabolic disorders in prenatal anti-Müllerian hormone (PAMH)-induced PCOS mice. Methods: First, we developed a prenatal AMH-induced PCOS-like model using pregnant C57BL/6N mice. Female offspring of mice were then subjected to the glucose tolerance test and insulin tolerance test pre- and post-treatment with metformin. H&E staining, serum hormone, and biochemical analyses were performed to determine the effects of metformin on metabolic abnormalities and liver damage in the PCOS-like model. To verify the specific mechanism of action of metformin, dehydroepiandrosterone (DHEA) and free fatty acids (FFAs; palmitic acid and oleic acid) induced alpha mouse liver 12 (AML-12) cells were used to establish a mouse liver cell model of adipose-like degeneration and lipid deposition. Results: Metformin effectively alleviated hepatic lipid accumulation in the PCOS mice. Furthermore, mitochondrial dysfunction and loss of redox homeostasis in the liver of PCOS mice were rescued upon metformin administration. Mechanistic insights reveal that metformin regulates mitochondrial autophagy in PCOS liver tissue via the activation of the Ethe1/Keap1/Nrf2/PINK1/Parkin pathway, thereby improving liver recovery in PCOS mice. Conclusions: Our findings highlight the role and mechanism of metformin in ameliorating abnormal mitophagy and lipid metabolic disorders in the PCOS mice livers and the potential of metformin for addressing NAFLD in PCOS mice.