OTUD5 Maintains STAT1/2 Stability and Promotes IFNγ-driven Intestinal Inflammation.

Abstract

Inflammatory bowel disease (IBD) is characterized by unresolved mucosal inflammation driven mainly by TNFα and/or IFNγ. While anti-TNFα biologics are a clinical mainstay, therapeutic resistance remains a significant hurdle. The molecular mechanisms that sustain inflammation in anti-TNFα non-responders are not fully understood. In human colon biopsies, we identified significant upregulation of the deubiquitinase OTUD5 in non-responders compared to responders, suggesting its involvement in therapy resistance. Using an intestinal epithelial cell (IEC)-specific Otud5 knockout mouse model, we show that Otud5 deficiency significantly alleviated the IFNγ-dependent colitis induced by dextran sulfate sodium (DSS), as evidenced by reduced weight loss and diminished infiltration of Ly6C+ inflammatory monocytes. Mechanistically, IFNγ induces OTUD5 expression through a non-transcriptional mechanism; in turn, OTUD5 stabilizes STAT1 and STAT2 by preventing their ubiquitination and subsequent degradation. This sustains IFNγ-ISGF3 signaling, which directly drives the expression of CCL8, a critical chemokine for monocyte recruitment. Targeting this pathway with a newly identified small-molecule inhibitor, CT1170, which exhibits potent activity against OTUD5, blocked the IFNγ-ISGF3-CCL8 axis, halted colitis progression, and suppressed colitis-elicited tumorigenesis. These findings were validated in human IBD organoids, where CT1170 effectively disrupted IFNγ-driven inflammatory signaling.