Cardiomyocyte pyroptosis and apoptosis play a vital role in the pathophysiology of several cardiovascular diseases. Our recent study revealed that gasdermin D (GSDMD) can promote myocardial I/R injury via the caspase-11/GSDMD pathway. We also found that GSDMD deletion attenuated myocardial I/R and MI injury by reducing cardiomyocyte apoptosis and pyroptosis. However, how GSDMD mediates cardiomyocyte apoptosis and protects myocardial function remains unclear. Here, we found that doxorubicin (DOX) treatment resulted in increased apoptosis and pyroptosis in cardiomyocytes and that caspase-11/GSDMD could mediate DOX-induced cardiotoxicity (DIC) injury. Interestingly, GSDMD overexpression promoted cardiomyocyte apoptosis, which was attenuated by GSDMD knockdown. Notably, GSDMD overexpression exacerbated DIC injury, impaired cardiac function in vitro and in vivo, and enhanced DOX-induced cardiomyocyte autophagy. Mechanistically, GSDMD regulated the activity of FAM134B, an endoplasmic reticulum autophagy receptor, by pore formation on the endoplasmic reticulum membrane via its N-terminus, thus activating endoplasmic reticulum stress. In turn, FAM134B interacted with autophagic protein LC3, thus inducing cardiac autophagy, promoting cardiomyocyte apoptosis, and aggravating DIC. These results suggest that GSDMD promotes autophagy and induces cardiomyocyte apoptosis by modulating the reaction of FAM134B and LC3, thereby promoting DIC injury. Targeted regulation of GSDMD may be a new target for the prevention and treatment of DIC.

心肌细胞焦亡和细胞凋亡在多种心血管疾病的病理生理学中起着至关重要的作用。我们最近的研究表明，gasdermin D (GSDMD) 可通过 caspase-11/GSDMD 途径促进心肌 I/R 损伤。我们还发现 GSDMD 缺失通过减少心肌细胞凋亡和细胞焦亡来减轻心肌 I/R 和 MI 损伤。然而，GSDMD如何介导心肌细胞凋亡和保护心肌功能尚不清楚。在这里，我们发现多柔比星 (DOX) 处理导致心肌细胞凋亡和细胞焦亡增加，并且 caspase-11/GSDMD 可以介导 DOX 诱导的心脏毒性 (DIC) 损伤。有趣的是，GSDMD 过表达促进了心肌细胞凋亡，而 GSDMD 敲低会减弱这种凋亡。值得注意的是，GSDMD 过表达加剧了 DIC 损伤，体外和体内心脏功能受损，并增强 DOX 诱导的心肌细胞自噬。从机制上讲，GSDMD 通过其 N 末端在内质网膜上形成孔隙来调节内质网自噬受体 FAM134B 的活性，从而激活内质网应激。反过来，FAM134B与自噬蛋白LC3相互作用，从而诱导心脏自噬，促进心肌细胞凋亡，加重DIC。这些结果表明 GSDMD 通过调节 FAM134B 和 LC3 的反应促进自噬并诱导心肌细胞凋亡，从而促进 DIC 损伤。靶向调控GSDMD可能成为防治DIC的新靶点。内质网自噬受体，通过其 N 末端在内质网膜上形成孔，从而激活内质网应激。反过来，FAM134B与自噬蛋白LC3相互作用，从而诱导心脏自噬，促进心肌细胞凋亡，加重DIC。这些结果表明 GSDMD 通过调节 FAM134B 和 LC3 的反应促进自噬并诱导心肌细胞凋亡，从而促进 DIC 损伤。靶向调控GSDMD可能成为防治DIC的新靶点。内质网自噬受体，通过其 N 末端在内质网膜上形成孔，从而激活内质网应激。反过来，FAM134B与自噬蛋白LC3相互作用，从而诱导心脏自噬，促进心肌细胞凋亡，加重DIC。这些结果表明 GSDMD 通过调节 FAM134B 和 LC3 的反应促进自噬并诱导心肌细胞凋亡，从而促进 DIC 损伤。靶向调控GSDMD可能成为防治DIC的新靶点。并加重 DIC。这些结果表明 GSDMD 通过调节 FAM134B 和 LC3 的反应促进自噬并诱导心肌细胞凋亡，从而促进 DIC 损伤。靶向调控GSDMD可能成为防治DIC的新靶点。并加重 DIC。这些结果表明 GSDMD 通过调节 FAM134B 和 LC3 的反应促进自噬并诱导心肌细胞凋亡，从而促进 DIC 损伤。靶向调控GSDMD可能成为防治DIC的新靶点。