NRF2-Targeted Therapy in Cardiovascular Disease Transitions from Systemic Activation to Precision Redox Medicine

The transcription factor Nuclear Factor Erythroid 2-Related Factor 2 (NRF2) governs cellular redox homeostasis and serves as a primary defense mechanism against oxidative stress-driven cardiac remodeling. Beyond basal antioxidant effects, NRF2 coordinates a broad defensive network that preserves mitochondrial bioenergetics, maintains proteostasis, and inhibits regulated cell death pathways, including necroptosis and ferroptosis. Despite robust efficacy in preclinical models, translating these findings to the clinic remains challenging. This review examines the molecular structure of the NRF2-KEAP1 axis, synthesizing evidence regarding its efficacy in ischemia–reperfusion injury and diabetic cardiomyopathy, while assessing the mechanisms of pathway repression and the liabilities of indiscriminate activation. We further review different pharmacological strategies, contrasting the clinical limitations of electrophiles with the potential of protein–protein interaction inhibitors. Finally, we discuss innovations such as cardiac-targeted delivery and biomarker-guided stratification, critically assessing whether these approaches can overcome safety barriers and emphasizing that rigorous validation is essential for clinical viability.