7,8-Dihydroxyflavone attenuates cisplatin-induced cardiomyocyte apoptosis and mitochondrial dysfunction via the p53/Nrf2 pathway

Abstract

Cisplatin (CDDP), while effective as a chemotherapeutic agent, poses significant cardiovascular risks that constrain its clinical utility. This study investigated the cardioprotective effects of 7,8-dihydroxyflavone (7,8-DHF) against CDDP-induced toxicity and explored the underlying molecular mechanisms in cardiomyocytes. CDDP exposure produced dose-dependent cytotoxic effects, characterized by reduced cell viability and elevated lactate dehydrogenase (LDH) release. Co-treatment with 7,8-DHF markedly attenuated CDDP-induced cellular damage by preventing cell death, minimizing LDH leakage, and preserving mitochondrial membrane potential (MMP). The compound also suppressed cardiomyocyte apoptosis, evidenced by fewer TUNEL-positive cells and restoration of the Bcl-2/Bax ratio. 7,8-DHF decreased mitochondrial reactive oxygen species (ROS) accumulation and enhanced cellular antioxidant defenses by upregulating nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1) signaling. Additionally, 7,8-DHF treatment decreased both 53BP1 foci formation and p53 protein expression. The specificity of these protective mechanisms was confirmed using pharmacological agents: Nutlin-3a (p53 activator) and Brusatol (Nrf2 inhibitor), both reversed the cardioprotective effects of 7,8-DHF, establishing the critical role of p53/Nrf2 pathway modulation. In summary, these findings demonstrate that 7,8-DHF protects against CDDP-induced cardiotoxicity by preserving mitochondrial function and preventing apoptosis through targeted inhibition of the p53 signaling and activation of Nrf2-mediated antioxidant responses in cardiomyocytes. Our study provides preliminary evidence for the potential of 7,8-DHF in mitigating CDDP-associated cardiac injury.