Yu Fengqin, Wu Tengzhen, Li Lina, Yang Bin, Yin Meixia
Department of Obstetrics and Gynecology, Nanjing Jinling Hospital, Nanjing, China.
Biotechnol Appl Biochem. 2025 Jun 18. doi: 10.1002/bab.2791.
Premature ovarian insufficiency (POI) is a condition characterized by the early depletion of ovarian follicles, leading to infertility and various systemic complications. Granulosa cell (GC) pyroptosis contributes significantly to the pathogenesis of POI. Orexin A, a neuropeptide involved in regulating wakefulness, has been shown to exert anti-inflammatory effects. This study investigates the potential protective role of orexin A in POI by targeting pyroptosis in ovarian GCs. We found that orexin A significantly reduced oxidative stress and the activation of the NLRP3 inflammasome in POI mice, thereby improving serum hormone levels and follicle count. Additionally, orexin A inhibited pyroptosis in cyclophosphamide (CTX)-treated KGN cells by downregulating NLRP3, caspase-1, and gasdermin D (GSDMD) expression. These effects were mediated through the activation of adenosine 5'-monophosphate-activated protein kinase (AMPK) signaling, which is known to regulate cellular metabolism and suppress inflammasome activation. In conclusion, orexin A has the potential to alleviate POI by inhibiting NOD-like receptor thermal protein domain-associated protein 3 (NLRP3) inflammasome-mediated pyroptosis and activating AMPK signaling, offering a promising therapeutic approach for POI treatment.
卵巢早衰（POI）是一种以卵巢卵泡过早耗竭为特征的病症，会导致不孕和各种全身并发症。颗粒细胞（GC）焦亡在POI的发病机制中起重要作用。食欲素A是一种参与调节觉醒的神经肽，已被证明具有抗炎作用。本研究通过靶向卵巢颗粒细胞焦亡来探究食欲素A在POI中的潜在保护作用。我们发现，食欲素A显著降低了POI小鼠的氧化应激和NLRP3炎性小体的激活，从而改善了血清激素水平和卵泡数量。此外，食欲素A通过下调NLRP3、半胱天冬酶-1和gasdermin D（GSDMD）的表达，抑制了环磷酰胺（CTX）处理的KGN细胞中的焦亡。这些作用是通过激活5'-单磷酸腺苷激活蛋白激酶（AMPK）信号介导的，已知该信号可调节细胞代谢并抑制炎性小体激活。总之，食欲素A有可能通过抑制NOD样受体热蛋白结构域相关蛋白3（NLRP3）炎性小体介导的焦亡并激活AMPK信号来缓解POI，为POI治疗提供了一种有前景的治疗方法。
