Gasdermin D mediates doxorubicin-induced cardiomyocyte pyroptosis and cardiotoxicity via directly binding to doxorubicin and changes in mitochondrial damage

Doxorubicin (Dox), as a widely used anthracycline antitumor drug, can cause severe cardiotoxicity. Cardiomyocyte death and inflammation are involved in the pathophysiology of Dox-induced cardiotoxicity (DIC). Gasdermin D (GSDMD) is known as a key executioner of pyroptosis, which is a pro-inflammatory pro-grammed cell death. We aimed to investigate the impact of GSDMD on DIC and systematically reveal its underlying mechanisms. Our findings indicated that Dox induced cardiomyocyte pyroptosis in a GSDMD-dependent manner by utilizing siRNA or overexpression-plasmid technique. We then generated GSDMD global knockout mice via CRISPR/Cas9 system and found that GSDMD deficiency reduced Dox-induced cardiomyopathy. Dox induced the activation of inflammatory cas-pases, which subsequently mediated GSDMD-N generation indirectly. Using molec-ular dynamics simulation and cell-free systems, we confirmed that Dox directly bound to GSDMD and facilitated GSDMD-N-mediated pyroptosis. Furthermore, GSDMD also mediated Dox-induced mitochondrial damage via Bnip3 and mito-chondrial perforation in cardiomyocytes. These findings provide fresh insights into the mechanism of how Dox-engaged GSDMD orchestrates adverse cardiotoxicity and highlight the prospects of GSDMD as a potential target for DIC. (Translational Research 2022; 248:36-50)

Automated summary

This study reveals the crucial role of gasdermin D (GSDMD) in doxorubicin-induced cardiotoxicity. Doxorubicin induces cardiomyocyte pyroptosis in a GSDMD-dependent manner, leading to cardiomyopathy. Deficiency of GSDMD reduces doxorubicin-induced cardiomyopathy. Additionally, GSDMD mediates doxorubicin-induced mitochondrial damage in cardiomyocytes.