The Nrf Family and Its Cardioprotective Potential: Mechanisms, Functions, and Therapeutic Perspectives

This review systematically elucidates the molecular mechanisms and therapeutic potential of nuclear factor erythroid 2-related factor (Nrf) family members in the cardiovascular system. As critical components of the CNC-bZIP transcription factor family, the Nrf family (including Nrf-2/NFE2L2, Nrf-1/NFE2L1, and Nrf-3/NFE2L3) orchestrates antioxidant response element (ARE)-dependent gene expression networks, playing pivotal roles in maintaining redox homeostasis, modulating inflammatory responses, improving mitochondrial function, and regulating programmed cell death (apoptosis, autophagy, and pyroptosis). Clinical data have demonstrated that in patients with myocardial infarction, the expression of Nrf-3 gene is significantly upregulated in myocardial cells within the infarcted area. Its high expression is associated with increased in-hospital mortality during the acute phase and accelerated progression of ventricular remodeling. Knockout of the Nrf-3 gene can reduce the acute-phase mortality of myocardial infarction, improve ventricular remodeling, and enhance cardiac function. Additionally, a crossover trial involving 19 participants showed that after 2 months of administration of olive oil by-product pâté tablets, the plasma Nrf-2 level in the subjects increased by 88.9% with concurrent improvement in cardiovascular risk factors. Collectively, these findings confirm the impact of the Nrf family on cardiovascular prognosis and its potential for intervention. Furthermore, we comprehensively analyze the regulatory functions of Nrf members in major cardiovascular pathologies, including myocardial ischemia-reperfusion injury, atherosclerotic plaque formation/stabilization, and heart failure progression. Based on recent advances, we also discuss innovative therapeutic strategies targeting the Nrf pathway, encompassing pharmacological activators, gene/epigenetic therapies, combinatorial approaches, and lifestyle interventions, thereby providing a theoretical framework and novel perspectives for the precision medicine of cardiovascular diseases.