YY1-NSUN7-m5C-HSPA1B axis drives polycystic ovary syndrome pathogenesis via epigenetic stabilization of HSPA1B mRNA.

Polycystic Ovary Syndrome (PCOS) is the most common endocrine disorder in reproductive-age women. Heat shock 70 kDa protein 1B (HSPA1B) is critical for stress response and inflammation, but its role in PCOS remains unknown. To validate HSPA1B as a key pathogenic gene in PCOS and investigate its regulatory mechanisms. Two PCOS datasets (GSE155489, granulosa cells; GSE54250, whole blood) were analyzed for differentially expressed genes. HSPA1B diagnostic value was assessed by ROC curve. Dihydrotestosterone (DHT)-induced KGN cell and dehydroepiandrosterone (DHEA)-induced mouse PCOS models were established. siRNA/adenoviral silencing, overexpression, methylated RNA immunoprecipitation (MeRIP), RNA immunoprecipitation (RIP), chromatin immunoprecipitation (ChIP), luciferase assay, actinomycin D chase, MTT, flow cytometry, ELISA, and Western blot were used to evaluate HSPA1B effects on granulosa cell function and dissect the YY1-NSUN7-m5C-HSPA1B axis. HSPA1B was identified as a core DEG, upregulated in patient blood and DHT-induced KGN cells (AUC = 0.9273). Silencing HSPA1B reversed DHT-induced injury: restored viability, reduced IL-6/IL-1β, decreased apoptosis, stabilized mitochondrial potential, reduced ROS, and inhibited M1 macrophage polarization (all P < 0.05). In vivo, HSPA1B silencing ameliorated ovarian pathology, corrected sex hormones (restored estradiol [E2], decreased testosterone [T]), and alleviated inflammation (all P < 0.01). Mechanistically, NSUN7 bound HSPA1B mRNA 3' UTR, enhancing stability via m5C methylation; Yin Yang 1 (YY1) activated NOP2/Sun RNA methyltransferase 7 (NSUN7) transcription by promoter binding. Rescue experiments established the YY1-NSUN7-m5C-HSPA1B axis. This study revealed the YY1-NSUN7- m5C -HSPA1B epigenetic axis in PCOS pathogenesis, providing a foundation for HSPA1B-targeted therapy.