Iron overload-induced ferroptosis in CD8+ T cells leads to functional abnormalities that promote endometriosis progression

BACKGROUND: Endometriosis (EM) exhibits localised iron overload. However, the contribution of ferroptosis to EM pathogenesis remains unclear. We investigated how iron overload affects CD8⁺ T cell immune function and the underlying ferroptotic mechanisms. METHODS: We collected eutopic and ectopic endometrial tissues from 57 patients with stage III-IV EM and eutopic tissues from 31 controls. Iron deposition was assessed by Prussian blue staining; CD8⁺ T cell infiltration by immunohistochemistry; and ferroptosis in CD8⁺ T cells by immunofluorescence and flow cytometry. In vitro and in vivo assays measured CD8⁺ T cell ferroptosis and endometrial stromal cell apoptosis via flow cytometry. Transwell assays evaluated cell migration. Gene and protein expression were analysed via RT-qPCR and Western Blot. We verified the effect of iron overload on the growth of lesions in vivo by constructing a mouse EM model. The role of CD8⁺ T cells in EM progression was tested using a reinfusion model. RESULTS: In ectopic EM lesions, CD8⁺ T cells were enriched yet functionally impaired, showing increased ferrous iron accumulation and lipid peroxidation alongside decreased GPX4 expression. In vitro, iron overload reduced CD8⁺ T cell viability, elevated lipid peroxidation, and induced mitochondrial damage-effects reversed by ferroptosis inhibitors. Iron overload upregulated p53 and downregulated xCT and GPX4; p53 inhibition blocked ferroptosis, indicating a p53-dependent pathway. In vivo EM models confirmed that excess iron compromises CD8⁺ T cell function and impairs their recruitment to lesion sites. CONCLUSIONS: Iron overload induces p53-mediated inhibition of xCT/GPX4, triggering ferroptosis in CD8⁺ T cells and leading to their dysfunction. These insights into ferroptosis-CD8⁺ T cell interactions in EM may guide the development of novel immunotherapeutic strategies.