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

Abstract

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.

Keywords: Cardiac rehabilitation; Cardioprotection; Cardio‐oncology; Chronic inflammation; Heart failure; Mitochondrial dysfunction; Nrf2; Oxidative stress.

Figure 1

Nrf2 pathway. In homeostatic conditions, Nrf2 is tightly regulated by Kelch‐like ECH‐associated protein 1 (Keap1), which promotes its ubiquitination and degradation. In response to oxidative stress, Nrf2 dissociates from Keap1, translocates to the nucleus, and binds to antioxidant response elements (AREs), inducing the expression of cytoprotective genes involved in redox homeostasis, detoxification, mitochondrial function and anti‐inflammatory response. Cul3, Cullin 3; NADPH, nicotinamide adenine dinucleotide phosphate; RBX1, RING‐box protein 1; Ub, ubiquitin.

Figure 2

The role of Nrf2 in the network of HF pathogenesis. Nrf2 dysregulation reduces the cellular intrinsic defences against oxidative stress, inducing mitochondrial dysfunction and precipitating pathological responses like ferroptosis. This condition of redox imbalance is further amplified by circulating elements (exosomes vehiculating miRNA and peripheral blood mononuclear cells) that systemically propagate ROS. The breakdown of Nrf2 pathway is associated with a state of chronic inflammation, with the abnormal activation of neurohormonal systems and ultimately with a marked susceptibility to ischaemia/reperfusion injury. As a result, pre‐clinical studies support the cardioprotective role of Nrf2 in several conditions, such as hypertension, diabetes, and cardiotoxicity, where the inhibition of Nrf2 response has been associated with the progression to cardiac dysfunction and ultimately HF. DCM, diabetic cardiomyopathy; IR, ischaemia–reperfusion.

Figure 3

Nrf2 and HFpEF pathogenesis. Reduced Nrf2 activity contributes to redox imbalance and inflammation, triggering fibrosis and activation of the renin–angiotensin–aldosterone system (RAAS). These interconnected pathways promote cardiac hypertrophy and diastolic dysfunction, key features in the development of HFpEF.