Cardiomyocyte-specific knockout of ADAM17 alleviates doxorubicin-induced cardiomyopathy via inhibiting TNFα-TRAF3-TAK1-MAPK axis

Doxorubicin as a commonly used anthracycline has become the cornerstone of chemotherapy in a wide range of cancers owing to its high efficacy. However, clinical applications of doxorubicin are limited mainly due to its toxic effects on myocardium but the pathogenic mechanism of doxorubicin-induced cardiomyopathy are poorly understood. ADAM17 is known as tumor necrosis factor α converting enzyme (TACE), and the cleavage of TNF-α by ADAM17 is a prerequisite for pro-inflammatory TNF-α activity, which raises a possibility that inhibition of ADAM17 may exert a beneficial effect on disease processes where TNF-α plays an essential role. Our previous research has shown that cardiomyocyte specific knockout of ADAM17 improves diabetic cardiomyopathy by modulating cardiomyocyte apoptosis. However, the relationship between ADAM17 and doxorubicin-induced cardiomyopathy is unclear.Through RNA sequencing analysis, we observed significant changes in the TNF signaling pathway genes in the heart tissue of mice with or without cardiomyocyte ADAM17 knockout.