Nuclear factor, erythroid 2 like 2 (NRF2)‐mediated disruption of iron homeostasis drives myocardial infarction progression

BACKGROUND AND PURPOSE: Disruptions in iron homeostasis are a hallmark of myocardial infarction (MI). Recent studies have implicated NRF2, a key transcriptional regulator of antioxidant and detoxification genes, in the regulation of iron metabolism, particularly in murine models of hepatic iron overload. Emerging evidence suggests that the NRF2/hepcidin/ferroportin axis plays a central role in co-ordinating cardiac iron and redox homeostasis. However, the underlying mechanisms remain poorly understood. EXPERIMENTAL APPROACH: In this study, we investigated the role of NRF2 in vivo using isoprenaline-induced MI and in vitro under cobalt chloride (CoCl₂)-induced hypoxia in H9c2 cardiomyocytes. KEY RESULTS: Our results show that MI activates NRF2 signalling through increased nuclear NRF2 levels and upregulation of its downstream targets, accompanied by elevated hepcidin expression without ferroportin1 (IREG1) changes, suggesting enhanced iron sequestration in myocardial tissue and cardiomyocytes. We observed that iron regulatory protein 1 (IRP1) was significantly down-regulated while IRP2 was up-regulated in isoprenaline-treated myocardium and hypoxia-exposed H9c2 cells. In vivo brusatol administration ameliorated isoprenaline-induced cardiac remodelling, shown by reduced infarct size and ECG alterations. Transcriptomic analysis of MI rats with brusatol showed downregulation of pathways in cardiac remodelling, fibrosis, hypoxia, inflammation, iron/glutathione metabolism, necroptosis and ferroptosis. In H9c2 cardiomyocytes under hypoxic conditions, brusatol increased ferroportin1 expression, decreased hepcidin levels and reduced intracellular labile iron, inhibiting ferritinophagy and cardiomyocyte death. CONCLUSION: Together, our findings uncover a novel regulatory role for NRF2 in myocardial iron metabolism under stress conditions, highlighting potential therapeutic avenues targeting the NRF2 pathway in MI.