Sodium danshensu mitigates myocardial ischemia-reperfusion injury by attenuating ferroptosis through Nrf2/SLC7A11/GPX4 pathway

Myocardial Ischemia-Reperfusion Injury (MI/RI) frequently occurs in individuals experiencing acute Myocardial Infarction (AMI) after undergoing reperfusion therapy. The process of Ferroptosis is intricately linked to MI/RI, and the nuclear factor erythroid 2-related factor 2 (Nrf2) is crucial in either promoting or impeding Ferroptosis. Sodium danshensu (SDSS), a water-soluble substance obtained from the Traditional Chinese Medicine known as Danshen, exhibits significant impacts on Oxidative Stress and Inflammation. However, the specific molecular mechanisms by which it addresses MI/RI are not fully understood. This study aims to investigate the therapeutic effects and underlying mechanisms of SDSS in mitigating MI/RI. Using both in vivo and in vitro models, we evaluated the impact of SDSS on Ferroptosis and its associated regulators. Myocardial injury was assessed via echocardiography, Masson's trichrome, and H&E staining. Mitochondrial function was examined through transmission electron microscopy and JC-1 staining. Expression levels of ferroptosis-related markers, including Nrf2, GPX4, and SLC7A11, were measured using Western blotting, immunohistochemistry, and immunofluorescence. The findings indicated that SDSS provided significant cardiac protection and reduced MI/RI by inhibiting Ferroptosis through modulation of the Nrf2 pathway, which in turn diminished oxidative stress and restored mitochondrial function in both in vivo and in vitro settings. Mechanistically, SDSS not only enhanced the levels of Nrf2 but also promoted its translocation into the nucleus, which in turn initiated the subsequent antioxidant defense processes. In summary, this research highlights that SDSS alleviates MI/RI by targeting the Nrf2/SLC7A11/GPX4 signaling pathway, indicating its potential as a therapeutic agent for Ferroptosis inhibition.