Cardiomyocyte GSDME Drives Doxorubicin-Induced Cardiotoxicity by Targeting the CCL2-CCR2 Axis

The use of doxorubicin (DOX), a wide-spectrum antineoplastic drug, is largely limited in clinical practice because of the less than satisfactory strategies available for the prevention and treatment of doxorubicin-induced cardiotoxicity (DIC). Although gasdermin E (GSDME) has been linked to the development of several cardiovascular diseases, the role of GSDME in DIC has not been thoroughly investigated. Here, we aimed to explore the role of GSDME in the development of DIC and develop efficient and feasible targets for managing DIC. We found that GSDME was upregulated in both DOX-treated murine hearts and isolated adult mouse cardiomyocytes. Conditional Gsdme knockout in cardiomyocytes, but not myeloid cells, attenuated DOX-induced cardiac remodeling, cardiac malfunction, and cardiac fibrosis. Cardiomyocyte-specific Gsdme knockout dampened DOX-induced cardiac CCL2-CCR2 signaling and inflammation, while CCL2 inhibition or CCR2+ macrophage depletion attenuated DIC. Mechanistically, GSDME facilitated mitochondrial injury in cardiomyocytes to release mtDNA and activated the STING/NFκB pathway, further targeting the CCL2-CCR2 axis and cardiac inflammation, thereby aggravating DIC. These findings identify GSDME as a potential therapeutic target for DIC.