The emerging role of Nrf2 in heart failure. From cardioprotection to therapeutic approaches

Heart failure (HF) is a multifactorial and pathophysiological complex syndrome, involving not only neurohormonal activation but also oxidative stress, chronic low-grade inflammation, and metabolic derangements. Central to the cellular defence against oxidative damage is nuclear factor erythroid 2-related factor 2 (Nrf2), a transcription factor that orchestrates antioxidant and cytoprotective responses. Preclinical in vitro and in vivo studies reveal that Nrf2 signalling is consistently impaired in HF, contributing to the progression of myocardial dysfunction. The loss of Nrf2 activity intersects a complex network of pathological processes involving neurohormonal activation, ischaemia-reperfusion injury, and sustained inflammation, exacerbating cardiac functional decline. Nrf2 deficiency diminishes resilience to clinical conditions such as hypertension, diabetic cardiomyopathy, and cancer therapy-related cardiotoxicity, favouring the transition from initial cardiac dysfunction to overt HF. Initial evidence supports the therapeutic potential of Nrf2 modulation. Lifestyle interventions such as exercise training, various natural compounds, and established cardiovascular agents (e.g. sodium-glucose cotransporter-2 inhibitors) have been shown to restore Nrf2 activity. This review analyses the emerging role of Nrf2 as both a key player in HF pathogenesis and a promising therapeutic target, highlighting available evidence across HF phenotypes and addressing the controversies surrounding its pharmacological modulation.