Urolithin A improves myocardial ischemia-reperfusion injury by attenuating oxidative stress and ferroptosis through Nrf2 pathway.

Ischemia/reperfusion (I/R) injury has been demonstrated to exert a significant role in acute myocardial infarction (AMI), which constitutes a crucial cause of AMI. Ferroptosis represents a novel form of cell death that is intimately linked to myocardial ischemia-reperfusion (MIR) injury. Urolithin A (UA), an intestinal metabolite of ellagitannins, has not been fully elucidated for its role in MIR injury. In the present study, we analyzed the effects of UA on ischemia-reperfusion-induced oxidative stress and ferroptosis both in vitro and in vivo, and explored the potential mechanisms of UA action. The results indicated that UA was capable of protecting the heart from ischemia-reperfusion injury and enhancing cardiac function both in vitro and in vivo. In addition, UA also attenuated oxidative stress, mitochondrial damage, and ferroptosis during MIR. Mechanistically, UA not only augmented the Nrf2 expression but also promoted Nrf2 entry into the nucleus and activated the downstream antioxidant defense system. Moreover, after the inhibition of Nrf2, the myocardial protective function of UA was lost, and its function of attenuating oxidative stress and ferroptosis was suppressed. In conclusion, we found that UA protected the heart from ischemia-reperfusion injury by attenuating oxidative stress and ferroptosis through the Nrf2 signaling pathway, suggesting that UA might be a potential therapeutic agent for the treatment of AMI.