Identification of A p300–SP1–BRD4 Transcriptional Axis as a Key Driver of AR Hyperactivation in Polycystic Ovarian Syndrome

ABSTRACT Persistent androgen receptor (AR) activation is an important contributor to polycystic ovary syndrome (PCOS) and is affected by transcriptional regulation via histone acetylation; however, the underlying mechanisms are partially understood. This study demonstrated that AR activation in ovarian granulosa cells (GCs) of both dehydroepiandrosterone (DHEA) and high‐fat diet‐induced PCOS mouse models correlated with a significant increase in the histone acetyltransferase p300 and histone acetylation. Conversely, GC‐specific p300 knockout or pharmacological inhibition with C646/A‐485 effectively reduced AR activation, histone 3 acetylation (H3K18ac/H3K27ac), and ovarian fibrosis in PCOS mice, highlighting p300 as a critical driver. ATAC‐seq and RNA‐seq identified “open” chromatin regions at the AR promoter in PCOS ovaries, corresponding with increased AR transcription and histone acetylation. p300, along with transcription factor SP1 and the acetyl‐reader BRD4, bound to H3K18ac and H3K27ac of the AR promoter in PCOS‐modeled ovaries and GCs, which was blocked by C646 and the SP1 inhibitor Plicamycin, respectively. Importantly, continuous AR activation by its ligand DHT largely diminished the anti‐fibrotic and ovarian‐protective effects of C646. These findings suggest that p300, SP1, and BRD4, form a critical transcriptional complex driving AR activation and PCOS development, and that targeting the p300/AR axis may present a promising therapeutic approach for treating PCOS.