Shang Yujie, Li Yunjun, Han Di, Deng Kun, Gao Wei, Wu Minghua
The Affiliated Cancer Hospital of Xiangya School of Medicine, Hunan Cancer Hospital, Central South University, Changsha, 410000, China.
School of Chinese Medicine, Hubei University of Chinese Medicine, Wuhan, 430065, China.
Adv Sci (Weinh). 2025 Jun;12(23):e2417717. doi: 10.1002/advs.202417717. Epub 2025 May 2.
Premature ovarian insufficiency (POI), defined by early loss of ovarian activity before the age of 40 years, is the leading cause of infertility and systematic aging in women, posing a public health challenge worldwide. However, its molecular etiology and therapeutic options are still lacking. Here, leucine-rich repeat containing 4 (LRRC4) is identified as a critical regulator of folliculogenesis expressed in granulosa cells (GCs), which contributes to ovarian reserve maintenance. LRRC4 deficiency triggers defective oocyte maturation and excessive follicular atresia through inhibition of GC differentiation and ultimately leads to POI. Mechanistically, LRRC4 balances mitochondrial fission and fusion to inhibit excessive mitophagy by promoting the K48-linked ubiquitination degradation of Yes-associated protein (YAP), thereby maintaining the metabolic homeostasis of mitochondrial aerobic respiration and glycolysis. Importantly, targeting LRRC4 normalized follicular development and ovarian function in POI model mice. In conclusion, these data reveal the novel pathogenesis of POI and suggest that LRRC4 is a potential target for the diagnosis and treatment of POI.
卵巢早衰（POI）是指在40岁之前卵巢活动过早丧失，是女性不孕和系统性衰老的主要原因，在全球范围内构成公共卫生挑战。然而，其分子病因和治疗选择仍然缺乏。在这里，富含亮氨酸重复序列4（LRRC4）被确定为在颗粒细胞（GCs）中表达的卵泡发生的关键调节因子，有助于维持卵巢储备。LRRC4缺乏通过抑制GC分化引发卵母细胞成熟缺陷和过度卵泡闭锁，最终导致POI。机制上，LRRC4通过促进Yes相关蛋白（YAP）的K48连接泛素化降解来平衡线粒体裂变和融合，从而抑制过度的线粒体自噬，从而维持线粒体有氧呼吸和糖酵解的代谢稳态。重要的是，靶向LRRC4可使POI模型小鼠的卵泡发育和卵巢功能正常化。总之，这些数据揭示了POI的新发病机制，并表明LRRC4是POI诊断和治疗的潜在靶点。
