Cellular senescence is closely associated with age-related diseases. Ovarian aging, a special type of organ senescence, is the pathophysiological foundation of the diseases of the reproductive system. It is characterized by the loss of integrity of the surface epithelium and a gradual decrease in the number of human ovarian surface epithelial cells (HOSEpiCs). To contribute to the research on delaying ovarian aging, we aimed to investigate the novel epigenetic mechanism of melatonin in protecting HOSEpiCs. We discovered that melatonin has antagonistic effects against the oncogene-induced senescence (OIS) of HOSEpiCs. Mechanistically, the oncogene Ras decreased the expression of YTHDF2, which is the reader of RNA-m⁶A, by stimulating the generation of reactive oxygen species (ROS). Moreover, we found that the suppression of YTHDF2 increased the expression of MAP2K4 and MAP4K4 by enhancing the stability of the transcription of their mRNAs, thereby upregulating the expression of the senescence-associated secretory phenotype (SASP) through the activation of the MAP2K4 and MAP4K4-dependent nuclear factor-κB (NF-κB) signaling pathways. We further determined that melatonin has antagonistic effects against the OIS of HOSEpiCs by inhibiting the ROS-YTHDF2-MAPK-NF-κB pathway. These findings provide key insights into the potential avenues for preventing and treating ovarian aging.

细胞衰老与年龄相关疾病密切相关。卵巢衰老是一种特殊的器官衰老，是生殖系统疾病的病理生理基础。它的特点是表面上皮的完整性丧失和人卵巢表面上皮细胞（HOSEpiCs）的数量逐渐减少。为了有助于延缓卵巢衰老的研究，我们旨在研究褪黑激素在保护 HOSEpiCs 中的新表观遗传机制。我们发现褪黑激素对 HOSEpiCs 的致癌基因诱导的衰老 (OIS) 具有拮抗作用。机制上，致癌基因 Ras 降低了 YTHDF2 的表达，YTHDF2 是 RNA-m ^{6的阅读器}A，通过刺激活性氧（ROS）的产生。此外，我们发现抑制YTHDF2通过增强其 mRNA 转录的稳定性来增加 MAP2K4 和 MAP4K4 的表达，从而通过激活 MAP2K4 和 MAP4K4 上调衰老相关分泌表型 (SASP )的表达。依赖核因子-κB (NF-κB) 信号通路。我们进一步确定褪黑激素通过抑制 ROS-YTHDF2-MAPK-NF-κB 通路对 HOSEpiCs 的 OIS 具有拮抗作用。这些发现为预防和治疗卵巢衰老的潜在途径提供了关键见解。