Trastuzumab (TRZ) is an anti-HER2 monoclonal antibody associated with significant survival benefits; however, its clinical utility is restricted by trastuzumab-induced cardiotoxicity (TIC). While the inhibition of HER2 induces mitochondrial dysfunction in cardiomyocytes, it is unclear whether mitochondrial quality control participates in trastuzumab-mediated cardiomyocyte pyroptosis. This study demonstrated that TRZ leads to a reduction in left ventricular systolic function, myocardial pyroptosis, and mitochondrial oxidative stress; alterations in the mitochondrial membrane potential; changes in mitochondrial permeability; mitochondrial dysfunction; and a decrease in mitochondrial biosynthesis in the murine heart. Supplementation with exogenous spermidine inhibits myocardial oxidative stress and mitochondrial dysfunction, and promotes mitochondrial biosynthesis in mice, thereby protecting cardiac function. Additionally, SIRT3 plays a protective role in TRZ-induced myocardial injury. In SIRT3 knockout mice, TRZ-induced cardiac injury was exacerbated, and mitochondrial damage was aggravated. In conclusion, these findings reveal the pathogenic mechanism underlying trastuzumab-induced cardiomyopathy and suggest a novel therapeutic target for preventing cardiotoxicity in HER2+ breast cancer treatment.
Keywords: mitochondrial biosynthesis; pyroptosis; spermidine; trastuzumab.
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