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Excessive macroautophagy/autophagy is one of the causes of cardiomyocyte death induced by cardiovascular diseases or cancer therapy, yet the underlying mechanism remains unknown. We and other groups previously reported that autophagy might contribute to cardiomyocyte death caused by sunitinib, a tumor angiogenesis inhibitor that is widely used in clinic, which may help to understand the mechanism of autophagy-induced cardiomyocyte death. Here, we found that sunitinib-induced autophagy leads to apoptosis of cardiomyocyte and cardiac dysfunction as the cardiomyocyte-specific Atg7−/+ heterozygous mice are resistant to sunitinib. Sunitinib-induced maladaptive autophagy selectively degrades the cardiomyocyte survival mediator CCN2 (cellular communication network factor 2) through the TOLLIP (toll interacting protein)-mediated endosome-related pathway and cardiomyocyte-specific knockdown of Ccn2 through adeno-associated virus serotype 9 (AAV9) mimics sunitinib-induced cardiac dysfunction in vivo, suggesting that the autophagic degradation of CCN2 is one of the causes of sunitinib-induced cardiotoxicity and death of cardiomyocytes. Remarkably, deletion of Hmgb1 (high mobility group box 1) inhibited sunitinib-induced cardiomyocyte autophagy and apoptosis, and the HMGB1-specific inhibitor glycyrrhizic acid (GA) significantly mitigated sunitinib-induced autophagy, cardiomyocyte death and cardiotoxicity. Our study reveals a novel target protein of autophagic degradation in the regulation of cardiomyocyte death and highlights the pharmacological inhibitor of HMGB1 as an attractive approach for improving the safety of sunitinib-based cancer therapy. [ABSTRACT FROM AUTHOR]