NRF2 signalling in endometriosis: A hormone-independent axis for fertility-preserving therapeutic innovation.

Endometriosis is a chronic inflammatory disease characterised by pain, infertility and recurrence. Current pharmacological management relies largely on hormonal suppression, which can reduce pain and disease activity but does not eradicate ectopic lesions, and symptoms often recur after treatment withdrawal. Adverse effects and incomplete responses further limit long-term use. Because hormonal therapies suppress ovulation and menstruation without improving spontaneous fertility, they are unsuitable for patients seeking pregnancy, underscoring the need for non-hormonal strategies that control lesions while preserving reproductive function. Recurrent bleeding, erythrocyte degradation and iron accumulation create an oxidative microenvironment linking ferroptosis dysregulation, chronic inflammation and defective immune clearance. NRF2 coordinates antioxidant defence, lipid-peroxide removal, iron and haem handling, and inflammatory and immune responses, but its effects are context dependent. To organise these divergent findings, we propose a testable framework of redox-adapted and redox-exhausted lesion states and consider how redox capacity, cellular compartment, intervention intensity and timing may shape NRF2-directed interventions. This review integrates NRF2 regulation with evidence on oxidative stress, ferroptosis, inflammation, immunity and reproductive-tissue protection in endometriosis. We distinguish direct disease evidence from mechanistic extrapolation, evaluate pharmacological, immune-informed and materials-based approaches for selective or local NRF2 modulation, and discuss cell-specific effects and cycle-dependent reproductive-tissue vulnerability. We further define key translational requirements, including human-lesion validation, predictive biomarkers, therapeutic thresholds, reproductive-safety assessment and cell-selective or lesion-restricted delivery. This framework provides testable questions and a staged basis for future preclinical and early translational studies.