Hyperuricemia exacerbates myocardial ischemia-reperfusion injury by inducing ferroptosis via NCOA4 and xCT-GPX4 axis dysregulation.

Hyperuricemia is an important independent risk factor for poor prognosis following myocardial ischemia-reperfusion injury (MI/RI), yet its precise molecular mechanisms remain incompletely understood.This study aimed to determine whether hyperuricemia aggravates MI/RI by promoting ferroptosis through enhanced oxidative stress and disrupted iron metabolism. Using both in vivo models (hyperuricemia-myocardial ischemia-reperfusion mice,MI/R) and in vitro systems (HL-1 cardiomyocytes subjected to oxygen-glucose deprivation/reoxygenation, OGD/R), we found that elevated uric acid (UA) levels led to increased reactive oxygen species production, mitochondrial dysfunction, and altered expression of key ferroptosis-related proteins. Specifically, nuclear receptor coactivator 4(NCOA4) expression was upregulated, while the levels of SLC7A11 (xCT), glutathione peroxidase 4(GPX4), and ferritin heavy chain 1(FTH1) were significantly reduced. Notably, treatment with ferroptosis inhibitors such as deferoxamine(DFO) and ferrostatin-1(Fer-1) effectively mitigated these pathological changes, underscoring the contribution of NCOA4-FTH1 and xCT-glutathione (GSH)-GPX4 signaling to hyperuricemia-aggravated MI/RI.