Abstract

Research question Whether peritoneal iron overload drives fibrosis in endometriosis (EMs) through Nrf2 pathway dysfunction and the resulting ferroptosis? whether electroacupuncture (EA) can intervene in this process? Design An EMs mouse model was established and subjected to EA intervention. Fibrosis, ferroptosis-related markers, Nrf2/Keap1 pathway activity, the peritoneal microenvironment, and systemic pathological indicators were systematically assessed using histological staining, molecular biology techniques, and biochemical analyses. Results Both eutopic and ectopic lesions in EMs mice exhibited significant fibrosis accompanied by pronounced ferroptosis. Mechanistically, the Nrf2 pathway was functionally inactivated in both lesion types, with impaired nuclear translocation. Notably, in eutopic lesions, this inhibition occurred independently of its classical regulatory protein Keap1, suggesting alternative regulatory mechanisms for Nrf2. EA treatment not only effectively suppressed lesion growth and alleviated fibrosis and ferroptosis but also specifically reversed the impairment of Nrf2 nuclear translocation and improved systemic inflammation and endocrine disturbances. Conclusions This study is the first to systematically demonstrate the pivotal role of the “Nrf2 pathway inactivation—ferroptosis—fibrosis” axis in EMs, particularly in eutopic endometrial lesions. Our findings not only provide a novel paradigm for understanding the pathological mechanisms of EMs but also confirm that EA exerts therapeutic effects by targeting this pathway, offering a solid experimental foundation for its clinical application.