Super-enhancer-driven SGK1 activates polyamine metabolism to promote autoimmune uveitis.

Abstract

Uveitis, a leading cause of blindness, is driven by dysregulated immune responses, particularly autoreactive T cells. Despite advances in understanding its pathogenesis, key regulatory mechanisms remain elusive. Here, we integrate the cleavage under targets and tagmentation (CUT&Tag) and single-cell RNA sequencing (scRNA-seq) to delineate the super-enhancer (SE) landscape and transcriptional profiles of CD4⁺ T cells in Vogt-Koyanagi-Harada (VKH) disease. We identify serum/glucocorticoid-regulated kinase 1 (SGK1) as a key SE-associated gene, substantially up-regulated in CD4⁺ T cells of VKH patients. Pharmacological inhibition of SGK1 markedly alleviates uveitis in mice. Mechanistically, SE-driven SGK1 expression activates the MEK1-ERK1/2-ODC1 axis, leading to aberrant polyamine metabolism and a skewed T helper 17 (T_H17)/regulatory T (T_reg) balance, whereas polyamine supplementation negates these therapeutic benefits, confirming SGK1's role in driving disease progression. Notably, through molecular docking and molecular dynamics simulations, we identified herbacetin as a natural inhibitor of SGK1. Herbacetin restores immune balance and mitigates disease severity, highlighting SGK1 as a promising therapeutic target for autoimmune uveitis.