Salidroside directly inhibits TNFAIP1, profoundly ameliorating ulcerative colitis in mice.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by mucosal damage and impaired epithelial barrier function. Current therapies often lack specificity or have significant side effects. TNF-α is a key pro-inflammatory cytokine in UC, inducing various proteins, including TNFAIP1. The absence of known direct inhibitors for TNFAIP1 has limited its exploration as a therapeutic target, despite its potential role in driving inflammation. This study aimed to validate TNFAIP1's pathogenic role and identify a first-in-class direct inhibitor.

Researchers integrated bioinformatics analysis, DSS-induced colitis models in Tnfaip1-knockout mice, and virtual screening to identify potential inhibitors. Cellular thermal shift assay (CETSA) and ubiquitination assays were performed to confirm direct interaction and effects on protein stability. Wild-type mice with DSS-induced colitis were orally administered Salidroside to assess its therapeutic efficacy. The study compared the effects of Salidroside administration to the protective phenotype observed in Tnfaip1-deficient mice.