Empagliflozin attenuates DOX-induced cardiotoxicity by inhibiting RIPK1-mediated endoplasmic reticulum stress and autophagy
Abstract
BACKGROUND
Doxorubicin (DOX), a classical chemotherapeutic agent, remains indispensable in cancer treatment but is limited by dose-dependent cardiotoxicity. Investigating strategies to mitigate DOX-induced cardiac damage is critical. Empagliflozin, a sodium-glucose co-transporter 2 (SGLT2) inhibitor, exhibits anti-inflammatory and antioxidant effects in cardiovascular disease. This study investigated empagliflozin's protective effects against DOX-induced cardiotoxicity and underlying mechanisms.
METHODS
DOX-induced cardiotoxicity models were established in male C57BL/6 J mice, with cardiac-specific RIPK1 overexpression achieved via adeno-associated virus (AAV9) technology. Cardiac function was assessed using echocardiography, and heart tissue was analyzed for injury, inflammation, oxidative stress, endoplasmic reticulum (ER) stress, and autophagy through various biochemical and molecular assays.
RESULTS
Empagliflozin alleviated DOX-induced cardiac dysfunction, reduced fibrosis, and suppressed systemic inflammation and oxidative stress in mice. Mechanistic studies revealed that empagliflozin mitigated DOX-induced cardiotoxicity by inhibiting ER stress and autophagy, as evidenced by the downregulation of BIP, p-IRE1, and ATF6 expression, alongside elevated p62 and reduced LC3BII/LC3BI levels. RIPK1 was identified as a crucial mediator of empagliflozin's cardioprotective effects, with similar protection observed using the RIPK1 inhibitor Nec-1. RIPK1 knockdown in cardiomyocytes…
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