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This study demonstrated that AR activation in ovarian granulosa cells (GCs) of both dehydroepiandrosterone (DHEA) and high\u2010fat diet\u2010induced PCOS mouse models correlated with a significant increase in the histone acetyltransferase p300 and histone acetylation. Conversely, GC\u2010specific p300 knockout or pharmacological inhibition with C646\/A\u2010485 effectively reduced AR activation, histone 3 acetylation (H3K18ac\/H3K27ac), and ovarian fibrosis in PCOS mice, highlighting p300 as a critical driver. ATAC\u2010seq and RNA\u2010seq identified \u201copen\u201d 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\u2010reader BRD4, bound to H3K18ac and H3K27ac of the AR promoter in PCOS\u2010modeled 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\u2010fibrotic and ovarian\u2010protective 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.<\/jats:p>","DOI":"10.1002\/advs.202518185","type":"journal-article","created":{"date-parts":[[2026,2,13]],"date-time":"2026-02-13T08:46:39Z","timestamp":1770972399000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Identification of A p300\u2013SP1\u2013BRD4 Transcriptional Axis as a Key Driver of AR Hyperactivation in Polycystic Ovarian Syndrome"],"prefix":"10.1002","volume":"13","author":[{"given":"Zhengquan","family":"Zhu","sequence":"first","affiliation":[{"name":"Department of Pain Management Nanjing Drum Tower Hospital Affiliated Hospital of Medical School Nanjing University  Nanjing China"},{"name":"Department of State Key Laboratory of Analytical Chemistry For Life Science and 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