HIF-1α-Nrf2 crosstalk in myocardial ischemia-reperfusion injury: a potential preconditioning-responsive protective network

Myocardial ischemia-reperfusion injury (MIRI) is a dynamic pathological process in which metabolic and mitochondrial disturbances during ischemia predispose the myocardium to oxidative damage upon reperfusion. This temporal coupling poses a fundamental limitation to single-pathway cardioprotection, as interventions directed at one stage of injury may fail to adequately address the evolving pathophysiological cascade. Hypoxia-inducible factor-1α (HIF-1α) and nuclear factor erythroid 2-related factor 2 (Nrf2), key regulators of hypoxic adaptation and cellular redox homeostasis, respectively, may constitute an interconnected protective network that spans the ischemia-reperfusion transition. HIF-1α promotes metabolic reprogramming and mitochondrial adaptation during ischemia, thereby reducing oxidative susceptibility, whereas Nrf2 enhances glutathione metabolism, peroxide detoxification, and resistance to lipid peroxidation during reperfusion. Emerging evidence further suggests the possibility of reciprocal crosstalk between these pathways, with HIF-1α reported to facilitate Nrf2 activation and Nrf2 to support HIF-1α transcriptional availability and protein stability. This coupling may enable preconditioning to establish metabolic and mitochondrial adaptation before ischemia while simultaneously building an antioxidant defense reserve for reperfusion, while sustained metabolic adaptation during early reperfusion provides transitional support for the recovery of oxidative metabolism, thereby limiting secondary oxidative injury. Compared with isolated pathway activation, coordinated HIF-1α-Nrf2 regulation may therefore provide broader and more temporally integrated cardioprotection by simultaneously reducing oxidative susceptibility and enhancing resistance to reperfusion stress. Pharmacological and non-pharmacological preconditioning studies further support the therapeutic potential of this network-based strategy, highlighting HIF-1α-Nrf2 crosstalk as a promising framework for optimizing cardioprotection in MIRI.