Sex-Based Differences in the Nrf2 Oxidative Stress Response: Implications for Precision Therapeutics

Nuclear factor erythroid 2–related factor 2 (Nrf2) is a central regulator of antioxidant defences, mitochondrial function, and cellular stress responses, making its pharmacological activation a compelling strategy for neurodegenerative, metabolic, and cardiovascular diseases. Emerging evidence reveals that biological sex profoundly shapes Nrf2 signalling, influencing basal activity, inducibility, and downstream functional outcomes. Females often exhibit higher Nrf2 target gene expression in liver and kidney, whereas males may be more susceptible to oxidative or metabolic stress due to androgen-mediated suppression of the Nrf2 pathway. Hormonal status, age, and tissue-specific receptor distribution further modulate these effects, suggesting that therapeutic responses to Nrf2 activators are inherently sex-dependent. Pharmacokinetic and pharmacodynamic differences, including CYP3A-mediated metabolism and body composition, may additionally influence systemic exposure and safety profiles. Despite clinical use of Nrf2 activators such as dimethyl fumarate and omaveloxolone, sex-stratified data on efficacy, dosing, and safety are scarce. This knowledge gap underscores the need for systematic evaluation of sex, hormonal milieu, and age in pharmacokinetic, pharmacodynamic, and clinical studies to ensure treatments are safe, effective, and equitable. Integrating these variables into research and clinical practice will optimise therapeutic benefits and minimise adverse events by accounting for patient-specific biology. • Biological sex is a key but overlooked determinant of Nrf2 signalling • Females show enhanced antioxidant programmes across tissues • Sex differences in pharmacokinetics/dynamics shape therapeutic efficacy and safety • Sex, hormonal status, and age should guide Nrf2 drug development