Sex-based differences in the NRF2 oxidative stress response: Implications for precision therapeutics

Area of Science:

• Molecular Biology
• Pharmacology
• Endocrinology

Background:

• Nuclear factor erythroid 2-related factor 2 (NRF2) is a key regulator of cellular defense mechanisms against stress.
• NRF2 pathway activation is a promising therapeutic strategy for various diseases, including neurodegenerative, metabolic, and cardiovascular conditions.
• Growing evidence indicates that biological sex influences NRF2 signaling pathways.

Purpose of the Study:

• To explore the profound impact of biological sex on NRF2 signaling.
• To investigate how sex-specific factors modulate NRF2 activity and therapeutic responses.
• To highlight the need for sex-stratified research in NRF2 activator studies.

Main Methods:

• Review of emerging evidence on sex differences in NRF2 signaling.
• Analysis of factors influencing NRF2 activity, including hormones, age, and tissue-specific expression.
• Examination of pharmacokinetic and pharmacodynamic sex-based variations.

Main Results:

• Females often show higher NRF2 target gene expression than males.
• Males may be more vulnerable to oxidative stress due to androgen-mediated NRF2 suppression.
• Hormonal status, age, and tissue distribution significantly modulate NRF2 effects, leading to sex-dependent therapeutic outcomes.

Conclusions:

• Therapeutic responses to NRF2 activators are inherently sex-dependent.
• Current clinical data lacks sex-stratified efficacy and safety information for NRF2 activators.
• Systematic evaluation of sex, hormonal milieu, and age is essential for optimizing NRF2-targeted treatments.