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<p>Polycystic ovary syndrome (PCOS) is characterized by oxidative stress (OS). This study reveals a novel epigenetic mechanism linking lysine acetyltransferase 5 (KAT5) and thrombospondin-1 (TSP-1) in PCOS pathogenesis. A meta-analysis of 50 clinical studies demonstrated elevated systemic oxidative markers (total oxidant status, nitric oxide, malondialdehyde) and reduced paraoxonase-1 levels in PCOS patients, alongside compromised total antioxidant capacity in follicular fluid. Bioinformatic analysis identified TSP-1 as a key downregulated gene in PCOS, and the hTFtarget database predicted KAT5 as an upstream regulator of TSP-1. In vitro, H₂O₂-induced oxidative stress in KGN granulosa cells suppressed TSP-1, KAT5, and H2AK5ac levels, which were restored by N-acetylcysteine (NAC). Mechanistically, KAT5 was found to regulate TSP-1 expression via H2AK5 acetylation at its promoter. Knockdown of KAT5 exacerbated oxidative stress, apoptosis, and senescence, while TSP-1 overexpression counteracted these effects. In a letrozole-induced PCOS rat model, ovarian tissues exhibited decreased H2AK5 acetylation, reduced KAT5 and TSP-1 expression, and impaired redox homeostasis. Interventions with N-acetylcysteine or TSP-1 ameliorated ovarian pathological changes, hormonal imbalances, oxidative stress, apoptosis, and cellular senescence. Collectively, these findings establish the KAT5-TSP-1 axis as a critical regulator of ovarian redox homeostasis, unveiling a novel epigenetic mechanism and proposing a dual-target therapeutic strategy for PCOS.</p>

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The KAT5-TSP-1 Axis Maintains Ovarian Redox Homeostasis and Is Impaired in Polycystic Ovary Syndrome

  • 期刊论文

  • 发表日期：

    2026年7月21日

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  • Qiu Jin,
  • Wei Yang,
  • Chao Wang,
  • Yu Liu,
  • Ruijing Wang,
  • Li Liu,
  • Xianghan Zhang,
  • Jin Yan,
  • Meimei Liu

摘要

Polycystic ovary syndrome (PCOS) is characterized by oxidative stress (OS). This study reveals a novel epigenetic mechanism linking lysine acetyltransferase 5 (KAT5) and thrombospondin-1 (TSP-1) in PCOS pathogenesis. A meta-analysis of 50 clinical studies demonstrated elevated systemic oxidative markers (total oxidant status, nitric oxide, malondialdehyde) and reduced paraoxonase-1 levels in PCOS patients, alongside compromised total antioxidant capacity in follicular fluid. Bioinformatic analysis identified TSP-1 as a key downregulated gene in PCOS, and the hTFtarget database predicted KAT5 as an upstream regulator of TSP-1. In vitro, H₂O₂-induced oxidative stress in KGN granulosa cells suppressed TSP-1, KAT5, and H2AK5ac levels, which were restored by N-acetylcysteine (NAC). Mechanistically, KAT5 was found to regulate TSP-1 expression via H2AK5 acetylation at its promoter. Knockdown of KAT5 exacerbated oxidative stress, apoptosis, and senescence, while TSP-1 overexpression counteracted these effects. In a letrozole-induced PCOS rat model, ovarian tissues exhibited decreased H2AK5 acetylation, reduced KAT5 and TSP-1 expression, and impaired redox homeostasis. Interventions with N-acetylcysteine or TSP-1 ameliorated ovarian pathological changes, hormonal imbalances, oxidative stress, apoptosis, and cellular senescence. Collectively, these findings establish the KAT5-TSP-1 axis as a critical regulator of ovarian redox homeostasis, unveiling a novel epigenetic mechanism and proposing a dual-target therapeutic strategy for PCOS.