HMGA1 Attenuates Doxorubicin-Induced Cardiomyocyte Pyroptosis By Inhibiting SOX9

Abstract Doxorubicin (DOX) is widely used as an anti-tumor drug with severe cardiotoxicity, encephalotoxicity, nephrotoxicity and so on, especially cardiotoxicity, which severely limit its application. Researchers have extensively studied the mechanisms of DOX-induced cardiotoxicity. However, the underlying mechanism of DOX-induced cardiotoxicity needs to be further evaluated. Studies reveal that High-mobility group AT-hook1 (HMGA1) and Sex-determining-region-Y (SRY)-related HMG box-containing protein 9 (SOX9) contribute to caspase-3-mediated apoptosis, but whether HMGA1 and SOX9 participate in caspase-3/gasdermin E (GSDME)-mediated pyroptosis remains unknown. This study was performed to investigate whether HMGA1 and SOX9 participate in DOX-induced cardiomyocyte pyroptosis induced by DOX in vitro, and to reveal the molecular mechanisms of HMGA1 and SOX9 in regulating DOX-induced cardiomyocyte pyroptosis via caspase/GSDME pathway. Results showed that the expression of HMGA1 is significantly up-regulated while SOX9 is down-regulated in HL-1 cells after DOX treatment. We found that both inhibition of HMGA1 by small interfering RNA (siRNA) and overexpression of SOX9 by transfection of SOX9 plasmid significantly promote cardiomyocyte pyroptosis induced by DOX. In addition, HMGA1 interacts with SOX9. Finally, our results show that silencing SOX9 reverses cardiomyocyte pyroptosis induced by silencing HMGA1 after DOX treatment.