Vaccarin Improves Myocardial Ischemia-Reperfusion Injury by Attenuating Oxidative Stress and Ferroptosis Through Reducing NOX4-Modulated JAK2/STAT3 Pathway Activation.

and glutathione disulfide while restoring the levels of glutathione, solute carrier family 7 member 11, and glutathione peroxidase 4. NADPH oxidase 4 (NOX4) was subsequently identified as a putative molecular target of vaccarin. Moreover, vaccarin inhibited H/R-induced activation of the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway in cardiomyocytes. NOX4 overexpression counteracted vaccarin-mediated suppression of JAK2/STAT3 signaling and blocked its antioxidative and antiferroptotic effects in H/R-treated cardiomyocytes. Collectively, these findings indicate that vaccarin confers cardioprotection against MI/R injury by suppressing oxidative stress and ferroptosis, at least partly through inhibition of NOX4-driven JAK2/STAT3 signaling. These results suggest that vaccarin may be a promising therapeutic candidate for the treatment of MI/R injury.