炎性程序性细胞死亡的炎性细胞死亡（pyroptosis）是由气孔形成的背膜裂解引发的，直接由气孔素（GSDM）的N-端子蛋白裂解而引发，以触发细胞内的内容物释放。它在哺乳动物的抗感染和抗肿瘤免疫反应中起着重要的作用。然而，炎性细胞死亡是否参与组织再生的调控仍然大部分未知。在本研究中，我们利用Hydra vulgaris作为研究模型，发现在头部和足部再生后，在切断部位激活了HyCARD2-HyGSDME介导的炎性细胞死亡信号。通过沉默HyGSDME或HyCARD2的表达，明显阻碍了Hydra的头部和足部再生。机制上，创伤部位的HyCARD2-HyGSDME轴的激活依赖于细胞内线粒体活性氧（mtROS），而去除这些活性氧则妨碍了Hydra头部再生。此外，发现HyCARD2-HyGSDME轴门控的炎性细胞死亡增强了Wnt3的初始分泌和上调表达。总之，这些发现表明气孔素门控的炎性细胞死亡对激发Wnt信号传递以促进Hydra组织再生至关重要，从而为动物界内气孔素家族的功能多样化提供了新见解。版权所有 © 2023 Elsevier出版。

Pyroptosis, an inflammatory form of programmed cell death, is directly executed by gasdermin (GSDM) depending on its N-terminal pore-forming fragment-mediated membrane-disrupting, triggering intracellular contents release, which plays important roles in mammalian anti-infection and anti-tumor immune responses. However, whether pyroptosis engages in the regulation of tissue regeneration remains largely unknown. Here, utilizing Hydra vulgaris as the research model, we found that an HyCARD2-HyGSDME-mediated pyroptosis signalling is activated in both head and foot regenerated tips after amputation. Impeding pyroptosis by knocking down the expression of either HyGSDME or HyCARD2 significantly hampered both head and foot regeneration in Hydra. Mechanistically, the activation of HyCARD2-HyGSDME axis at wound sites is dependent of intracellular mitochondrial reactive oxygen species (mtROS), the removing of which hindered Hydra head regeneration. Moreover, the HyCARD2-HyGSDME axis-gated pyroptosis was found to enhance the initial secretion and upregulated expression of Wnt3. Collectively, these findings indicate that gasdermin-gated pyroptosis is critical for the evoking of Wnt signalling to facilitate Hydra tissue regeneration, which provides insights into functional diversification within the gasdermin family in the animal kingdom.Copyright © 2023. Published by Elsevier Ltd.