Follicular atresia significantly impairs female fertility and hastens reproductive senescence. Apoptosis of granulosa cells is the primary cause of follicular atresia. Pyroptosis and necroptosis, as additional forms of programmed cell death, have been reported in mammalian cells. However, the understanding of pyroptosis and necroptosis pathways in granulosa cells during follicular atresia remains unclear. This study explored the effects of programmed cell death in granulosa cells on follicular atresia and the underlying mechanisms. The results revealed that granulosa cells undergo programmed cell death including apoptosis, pyroptosis, and necroptosis during follicular atresia. For the first time, we identified the formation of a PANoptosome complex in porcine granulosa cells. This complex was initially identified as being composed of ZBP1, RIPK3, and RIPK1, and is recruited through the RHIM domain. Additionally, we demonstrated that caspase-6 is activated and cleaved, interacting with RIPK3 as a component of the PANoptosome. Heat stress may exacerbate the activation of the PANoptosome, leading to programmed cell death in granulosa cells. Our data identified the formation of a PANoptosome complex that promoted programmed cell death in granulosa cells during the process of follicular atresia. These findings provide new insights into the molecular mechanisms underlying follicular atresia.

中文翻译：

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PANoptosome 的组装和激活促进滤泡闭锁期间猪颗粒细胞程序性细胞死亡


毛囊闭锁显着损害女性生育能力并加速生殖衰老。颗粒细胞凋亡是滤泡闭锁的主要原因。细胞焦亡和坏死性凋亡作为程序性细胞死亡的另一种形式，已在哺乳动物细胞中报道。然而，对滤泡闭锁期间颗粒细胞的焦亡和坏死性凋亡途径的理解仍不清楚。本研究探讨了颗粒细胞程序性细胞死亡对滤泡闭锁的影响及其潜在机制。结果显示，颗粒细胞在滤泡闭锁期间经历程序性细胞死亡，包括细胞凋亡、焦亡和坏死性凋亡。我们首次在猪颗粒细胞中鉴定了 PANoptosome 复合物的形成。该复合物最初被鉴定为 由 ZBP1 、 RIPK3 和 RIPK1 组成，并通过 RHIM 结构域募集。此外，我们证明 caspase-6 被激活和裂解，作为 PANoptosome 的一个组成部分与 RIPK3 相互作用。热应激可能会加剧 PANoptosome 的激活，导致颗粒细胞中的程序性细胞死亡。我们的数据确定了 PANoptosome 复合物的形成，该复合物在滤泡闭锁过程中促进颗粒细胞的程序性细胞死亡。这些发现为滤泡性闭锁的分子机制提供了新的见解。