Salvianic Acid A Regulates Ferroptosis by Activating the Nrf2-GPX4 Pathway Through EGFR to Protect Myocardial Ischemia-Reperfusion Injury

Objective: Salvianic acid A, known for its potent cardioprotective effects, is a promising therapeutic agent for myocardial ischemia-reperfusion (I/R) injury, a condition where Ferroptosis plays a critical role. This study aims to explore the effect of Salvianic acid A on I/R injury through EGFR-Nrf2-GPX4-mediated Ferroptosis.

Methods: The levels of ROS, GSH, GSSG, Fe²⁺, the state of Ferroptosis, the expression and localization of Nrf2, and the expression of EGFR were all detected in hypoxia/reoxygenation (H/R) cells. The Nrf2 inhibitor ML385 and siRNA-EGFR were used to confirm the involvement of EGFR/Nrf2 in protecting cardiomyocytes from H/R-induced Ferroptosis. Additionally, the regulatory effect of Salvianic acid A on EGFR/Nrf2/GPX4 were analyzed in the I/R animal model with EGFR inhibitors/agonists.

Results: Salvianic acid A inhibited ROS, Fe²⁺, GSH, GSSG, GSH/GSSG, and promoted GPX4 and SLC7A11 expressions in H/R cells. Further experiments demonstrated that Salvianic acid A promoted Nrf2 nuclear translocation and expression to inhibit Ferroptosis, which was abolished by the Nrf2 inhibitor ML385. In addition, the molecular docking indicated that Salvianic acid A has a good binding activity with EGFR, and cell experiments also confirmed that Salvianic acid A promoted EGFR expression, which was required for its subsequent activation of Nrf2 and inhibition of Ferroptosis, as verified by siRNA-EGFR. In vivo experiments showed that Salvianic acid A alleviated myocardial injury, inhibited Ferroptosis, and this improvement was related to the regulation of NRF2-GPX4 by EGFR.

Conclusion: Salvianic acid A mediated Ferroptosis through the EGFR-regulated NRF2-GPX4 pathway, ultimately improving myocardial I/R injury.