HDAC2/Parkin axis regulates mitochondrial dysfunction and mitophagy in polyendocrine metabolic ovarian syndrome

To explore the function and underlying mechanism of histone deacetylase 2 (HDAC2)/Parkin axis in dihydrotestosterone (DHT)-induced mitochondrial dysfunction and mitophagy in granulosa cells and its potential as a therapeutic target for polyendocrine metabolic ovarian syndrome (PMOS). KGN cells were treated with DHT to establish a PMOS cell model, and HDAC2 or Parkin was silenced using shRNA. Mitochondrial ROS, membrane potential, mtDNA levels, and mitophagy-related proteins (PINK1, Parkin, LC3B) were assessed by immunofluorescence, Western blot, and co-immunoprecipitation. In vivo, PMOS was induced in rats by the combination of DHEA and a high‑fat diet, and the HDAC inhibitor SAHA was administered. Estrous cycles, endocrine and metabolic parameters, ovarian morphology, and mitophagy-related protein expression were evaluated. DHT-treated KGN cells showed increased mitochondrial ROS, diminished membrane potential and mtDNA content, as well as reduced levels of Parkin, PINK1, and the LC3B-II/LC3B-I ratio, suggesting mitochondrial dysfunction and potential impairment of mitophagy. HDAC2 knockdown alleviated these defects, whereas Parkin knockdown reversed the protective effects of HDAC2 depletion. Co-immunoprecipitation analysis revealed that HDAC2 interacts with Parkin and modulates its acetylation. In PMOS rats, SAHA treatment improved estrous cyclicity, decreased luteinizing hormone (LH), testosterone, anti-Müllerian hormone (AMH), and homeostatic model assessment of insulin resistance (HOMA-IR) levels, restored ovarian morphology, and increased the expression of Parkin, PINK1, and the LC3B-II/LC3B-I ratio, while reducing HDAC2 levels, suggesting enhanced mitophagy. HDAC2 may contribute to DHT-induced mitochondrial dysfunction in granulosa cells potentially through deacetylation of Parkin and suppression of PINK1/Parkin-mediated mitophagy-related protein expression. HDAC inhibition by SAHA may restore mitophagy and alleviate endocrine and metabolic abnormalities, indicating that the HDAC2/Parkin axis is a potential therapeutic target for PMOS.