Inflammation impairs fertility and oocyte quality in systemic lupus erythematosus by triggering oxidative stress-mediated ferroptosis.

Systemic lupus erythematosus (SLE) is an autoimmune disorder associated with impaired female fertility, as suggested by our previous clinical cohort data. However, the intrinsic mechanisms underlying oocyte quality deterioration remain incompletely understood. Using a chronic SLE mouse model, we show that SLE-associated inflammation is accompanied by impaired oocyte maturation, reduced developmental competence, and mitochondrial dysfunction, together with increased oxidative stress and ferroptosis-related alterations, an iron-dependent process characterized by lipid peroxidation. Pharmacological interventions revealed that both hydroxychloroquine and melatonin attenuated inflammation- and oxidative stress-associated abnormalities and partially improved oocyte developmental outcomes. In addition, inhibition of ferroptosis using ferrostatin-1 ameliorated ferroptosis-associated alterations and partially restored meiotic maturation and oocyte quality. Together, these findings establish a mechanistic link between SLE-induced inflammation, oxidative stress, ferroptosis, and impaired oocyte developmental competence. These results provide a framework for understanding inflammation-associated oxidative stress and ferroptosis-related alterations in SLE-associated reproductive dysfunction and may inform future therapeutic exploration.