ACE2 ameliorates DOX-induced cardiotoxicity by suppressing excessive autophagy via the AMPK/mTOR signaling pathway

Doxorubicin (DOX) cardiotoxicity involves dysregulated autophagy, yet the role of ACE2 in this process remains unclear. We aimed to determine if ACE2 protects against DOX-induced injury by modulating the AMPK/mTOR-autophagy axis. DOX-induced cardiotoxicity was established in mice and primary cardiomyocytes. The effects of modulating ACE2 and mTOR signaling were investigated using the agonist Diminazene Aceturate (DIZE), inhibitor MLN-4760, activator MHY1485 (MHY), and inhibitor Rapamycin (Rapa). Cardiac injury, apoptosis, autophagy, and key molecules in the RAS and AMPK/mTOR pathways were evaluated. DOX induced cardiac dysfunction, apoptosis, and excessive autophagy, accompanied by ACE2 downregulation, AMPK activation, and mTOR inhibition. ACE2 activation via DIZE reversed these pathologies both in vivo and in vitro. Mechanistically, the cardioprotective effects of DIZE were mimicked by mTOR activation and, importantly, abolished by mTOR inhibition with Rapamycin. Our findings demonstrate that ACE2 protects against DOX-induced cardiotoxicity by suppressing excessive autophagy. This effect is causally dependent on its ability to inhibit AMPK and activate mTOR signaling. Thus, targeting the ACE2-mTOR axis represents a promising therapeutic strategy to mitigate DOX cardiotoxicity.