Parthenolide Mitigates Doxorubicin‐Induced Cardiotoxicity in Rats With Associated Activation of Nrf2 and Inhibition of Ferroptosis

Doxorubicin (DOX) is a widely used anticancer agent, but its clinical utility is limited by significant cardiotoxicity. Parthenolide (PTL), a sesquiterpene lactone, has garnered significant attention due to its broad pharmacological potential. This study aimed to investigate the potential cardioprotective effects of PTL against DOX-induced cardiotoxicity in rats, focusing on its impact on Nuclear factor erythroid 2-related factor 2 (Nrf2) signaling and ferroptosis. Male Sprague-Dawley rats were divided into a control group, a DOX group, and DOX + PTL (10 mg/kg, 25 mg/kg, or 50 mg/kg) groups. DOX (4 mg/kg) was administered via intraperitoneal injection once weekly for 4 weeks. Cardiac function was assessed using echocardiography, and histopathological changes were examined through hematoxylin and eosin and Masson trichrome staining. Oxidative stress markers, inflammatory cytokines, and ferroptosis-related proteins-including acyl-CoA synthetase long-chain family member 4 (ACSL4), NADPH oxidase 4 (Nox4), glutathione peroxidase 4 (GPX4), and solute carrier family 7 member 11 (SLC7A11)-were measured by ELISA and Western blotting. Additionally, Nrf2 and its downstream targets were analyzed to elucidate the molecular mechanisms underlying PTL's effects. PTL treatment significantly improved DOX-induced cardiac dysfunction, as evidenced by improved echocardiographic parameters and reduced histopathological damage. PTL also markedly decreased oxidative stress and inflammatory cytokines, while upregulating Nrf2 signaling and downregulating ferroptosis-related protein expression. These results suggested that the cardioprotective effects of PTL might be associated with the activation of Nrf2 signaling and suppression of ferroptosis. PTL demonstrated significant cardioprotective effects against DOX-induced cardiotoxicity, likely through Nrf2 activation and ferroptosis inhibition. PTL is a promising therapeutic agent for mitigating DOX-induced cardiac dysfunction.