NRF2 links inflammatory signaling with ferroptotic vulnerability and IFN-γ–STAT1 responsiveness in endometrial carcinoma

Endometrial carcinoma (EC) exhibits substantial molecular heterogeneity, and the mechanisms linking stress adaptation to immune evasion remain incompletely understood. Although chronic inflammatory signaling and ferroptosis resistance have each been implicated in EC progression, how these processes are integrated with antitumor immunity remains unclear. Here, we identify nuclear factor erythroid 2-related factor 2 (NRF2) as a tumor-intrinsic regulator linking inflammatory signaling, ferroptotic vulnerability, and immune responsiveness in EC. Integrative transcriptomic analyses identified NF-κB signaling as a prominent inflammatory program associated with adverse clinical features, while NRF2-associated activity was increased in malignant epithelial compartments. Pharmacological perturbation and TNF-α stimulation supported an association between NF-κB-associated signaling and NRF2 expression under the conditions examined. Genetic NRF2 depletion increased sensitivity to ferroptotic stress, accompanied by disruption of SLC7A11/GPX4-associated defenses, increased ACSL4 expression, lipid peroxidation, labile iron, and mitochondrial oxidative stress. NRF2 depletion also increased STAT1 abundance and activity, enhanced nuclear STAT1 accumulation, and increased responsiveness to exogenous IFN-γ. These changes were accompanied by remodeling of a STAT1-associated antigen-presentation program, including increased NLRC5 and altered IRF1 expression, together with increased MHC-I expression. Under IFN-γ stimulation, NRF2 depletion further enhanced STAT1-associated responses and ferroptosis-associated stress. In an immunocompetent CT26 surrogate tumor model, NRF2 depletion was associated with reduced tumor growth, increased CD8-positive and granzyme B-positive signals, and greater tumor control during anti-PD-1 treatment. Analyses of human UCEC datasets further showed an association between NRF2-related activity and CD8-positive T-cell infiltration. Together, these findings support NRF2 as a tumor-intrinsic regulatory node linking inflammatory adaptation with ferroptotic vulnerability and immune responsiveness in EC.