SLC7A11 deficiency exacerbates systemic lupus erythematosus by inducing instability and ferroptosis in regulatory T cells.

Systemic lupus erythematosus (SLE) is an autoimmune disease posing a significant threat to human health. Regulatory T cells (Tregs) are crucial for immune homeostasis. Dysfunction of Tregs have been demonstrated in SLE, but underlying mechanisms remain largely unclear. Here, we observe that peripheral Treg numbers and SLC7A11 expression in Tregs are reduced in SLE, with SLC7A11 levels negatively correlates with disease activity. Treg-specific SLC7A11 deletion impairs their stability and differentiation, promotes a pro-inflammatory phenotype, thereby aggravating autoantibody production and lupus progression in mice. Mechanistically, mild SLC7A11 inhibition stabilizes HIF-1α, enhances glycolysis and increases pro-inflammatory cytokines in Tregs. Severe SLC7A11 inhibition causes excessive lipid peroxidation and ferroptosis. In summary, our findings suggest that SLE Tregs with reduced SLC7A11 expression may undergo varying degrees of damage. Specifically, mild SLC7A11 deficiency drives glycolysis and Treg instability, whereas severe deficiency triggers ferroptosis. Upregulating SLC7A11 expression may be a promising therapeutic strategy for SLE.