Epidermal growth factor receptor inhibition alleviates cardiac ischemia/reperfusion injury through preventing mitochondrial dysfunction and ferroptosis via Rho Family GTPase 3/5' AMP-activated protein kinase axis.

Previous studies have found that the underlying mechanisms of myocardial ischemia/reperfusion injury (MIRI) are complex and involve various regulated cell death including ferroptosis. The focus of this study was to elucidate the exact mechanism of MIRI and the role of the Epidermal growth factor receptor (EGFR)/Rho family GTPase 3 (RND3)/5' AMP-activated protein kinase (AMPK) pathway in MIRI-induced ferroptosis and mitochondrial dysfunction. The in vivo and in vitro I/R injury models were performed. Our results indicated that EGFR inhibition could effectively attenuate MIRI through inhibiting ferroptosis, as showed by elevated cell viability, increased LDH activity and apoptosis, prevented iron overload and abnormal lipid metabolism, maintained cardiac and mitochondrial function, reduced infarct size, decreased reactive oxygen species (ROS) and TUNEL-positive cells. Importantly, EGFR inhibition could upregulated the protein level of RND3, which could directly interact with AMPK and cause the phosphorylation and activation of it, then attenuating ferroptosis and mitochondrial dysfunction induced by MIRI. Finally, the effects of EGFR inhibition were abolished after pretreatment with pAd/RND3-shRNA or Compound C (an AMPK inhibitor). According to these findings, we conclude that the EGFR/RND3/AMPK axis plays a key role in the pathological process of MIRI and that EGFR inhibition could attenuate ferroptosis and mitochondrial dysfunction triggered by MIRI via activating the RND3/AMPK pathway.