ETV1 Drives CD4+ T Cell-Mediated Intestinal Inflammation in Inflammatory Bowel Disease Through Amino Acid Transporter Slc7a5.

Excessive CD4+ T cell responses drive inflammatory bowel disease (IBD), yet the transcriptional mechanisms underlying their dysfunction remain incompletely understood. Here, it is demonstrated that E-twenty-six variant transcription factor 1 (ETV1) is upregulated in IBD patients and positively correlates with disease severity. Etv1 deficiency impairs CD4+ T cell activation, proliferation, and T helper 17 (Th17) cell differentiation, thereby ameliorating TNBS-induced colitis. Moreover, Etv1 deficiency attenuates CD45RBhighCD4+ T cell-induced colitis, characterized by a reduction in pathogenic CD4+ T cells in the intestinal mucosa. Pharmacological inhibition of ETV1 ameliorates colitis in recombination activating gene 1-deficient mice and suppresses human IBD T cell responses ex vivo. Mechanistically, Etv1 binds to the promoter of the gene encoding the amino acid transporter solute carrier family 7 member 5 (Slc7a5), enhancing its expression and subsequent amino acid uptake to fuel T cell pathogenicity. Restoring Slc7a5 expression rescues the proliferation, differentiation, and colitogenic function of Etv1-deficient CD4⁺ T cells. Clinically, SLC7A5 is upregulated in IBD, and its blockade ameliorates T cell-driven colitis in vivo. Collectively, the results establish a critical role for the ETV1-Slc7a5 axis in driving pathogenic CD4⁺ T cell responses in IBD, highlighting this pathway as a novel therapeutic target.