Babao Dan Improves Doxorubicin-Induced Cardiomyopathy by Activating Nrf2/GPX4 Signaling Pathway

OBJECTIVE: To investigate the protective effects and underlying mechanisms of Babao Dan (BBD) against doxorubicin (Dox)-induced cardiomyopathy (DIC). METHODS: A zebrafish model of DIC alongside an in vitro model of cardiomyocyte injury induced by Dox was utilized to elucidate the protective effects of BBD against DIC. The zebrafish and cell models were divided into control, Dox, and BBD (low-, medium-, and high-dose) plus Dox treatment groups. Reactive oxygen species (ROS) and malondialdehyde (MDA) content were determined by commercial kits. Nrf2/GPX4 signaling activity was assessed by Western blot and RT-qPCR. A comprehensive network pharmacology analysis was conducted to explore the potential mechanisms of action of BBD on DIC. RESULTS: Compared with Dox group, BBD treatment significantly reduced ROS levels and decreased MDA content in zebrafish (P<0.01), indicating ameliorated oxidative stress, which contributed to a reduction in Dox-induced cardiac injury. Notably, BBD was found to inhibit cardiomyocyte ferroptosis by restoring mitochondrial function in vitro. Network pharmacology analysis identified 4 core network genes, including Nrf2, which is pivotal in linking oxidative stress with ferroptosis, along with 6 key active components of BBD. Molecular docking and dynamics simulations demonstrated that these active components exhibit a strong binding affinity with the identified core targets. CONCLUSIONS: BBD effectively activates the Nrf2/GPX4 signaling pathway, thereby inhibiting cardiomyocyte ferroptosis and mitigating DIC. These insights provide a theoretical foundation for the future exploration of BBD as a preventive and therapeutic agent against Dox-related cardiotoxicity.