Gasdermin D Mediates Endoplasmic Reticulum Stress by FAM134B to Regulate Cardiomyocyte Autophagy and Apoptosis in Doxorubicin-induced Cardiotoxicity

Abstract 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 caspase-11/GSDMD pathway. Furthermore, 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. We here evaluated that doxorubicin (DOX) treatment resulted in significantly increased apoptosis instead of pyroptosis in cardiomyocytes. Interestingly, GSDMD overexpression promoted cardiomyocyte apoptosis, and GSDMD knockdown attenuated cardiomyocyte apoptosis. Notably, GSDMD overexpression exacerbated DOX-induced cardiotoxicity (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.