ADP-ribosylation factor 1 sustains regulatory T cell function and mucosal immune homeostasis in ulcerative colitis.

Dysregulation of regulatory T cells (Tregs) is a hallmark of immune imbalance in ulcerative colitis (UC), in which their suppressive function relies heavily on post-translational modifications and the stabilization of the transcription factor Foxp3. However, the upstream regulatory mechanisms remain poorly understood. Here, we identify ADP-ribosylation factor 1 (Arf1) as a key regulator of Treg function. Clinical samples from UC patients revealed an inverse correlation between ARF1 expression in Tregs and disease severity. Using a Treg-specific Arf1 knockout mouse model, we demonstrate that Arf1 deficiency impairs induced Treg (iTreg) differentiation, disrupts suppressive function, and aggravates T cell transfer-induced colitis. Mechanistically, Arf1 sustains mitochondrial integrity and represses histone deacetylase 9 (Hdac9), thereby enhancing FOXP3 acetylation and protein stability. These findings establish Arf1 as a critical upstream modulator of Treg cell function and intestinal immune homeostasis, and highlight the ARF1-HDAC9-FOXP3 axis as a promising target for Treg-based therapeutic strategies in UC.