What question did this study set out to answer?

The study aims to explore how USP43 affects intestinal inflammation, particularly in the context of ulcerative colitis.

May 18, 2026Open Access

USP43 Inhibits Intestinal Inflammation via TRAF4-mediated NF-κB Signaling

Puntos clave

The study aims to explore how USP43 affects intestinal inflammation, particularly in the context of ulcerative colitis.
Conducted RNA-seq and proteome analyses to assess USP43 expression in colitis models and UC patients.
Utilized LPS-treated RAW264.7 cells to investigate the effects of USP43 overexpression and knockdown on NF-κB activation.
Examined the interaction between USP43 and TRAF4, and its effects on inflammatory cytokine production.
USP43 expression was significantly lower in DSS-induced colitis and UC patients compared to healthy controls.
USP43 overexpression inhibited NF-κB p65 phosphorylation and proinflammatory cytokine production, while knockdown had the opposite effect (p<0.05).
TRAF4 overexpression partially reversed the increased NF-κB activation caused by USP43 knockdown, indicating a regulatory mechanism.

Resumen

Ulcerative colitis (UC) is a chronic inflammatory intestinal disorder; however, its exact pathophysiological mechanisms remain elusive. Through integrated RNA-seq and proteome analyses, we revealed that ubiquitin-specific protease 43 (USP43) expression is significantly decreased in dextran sulfate sodium (DSS)-induced colitis. USP43 expression was also lower in UC patients than that in healthy controls. Furthermore, USP43 deficiency in mice exacerbated DSS-induced colitis. In lipopolysaccharide (LPS)-treated RAW264.7 cells, USP43 overexpression inhibited, whereas USP43 knockdown promoted the phosphorylation of p65 and the production of proinflammatory cytokines; NF-κB-specific inhibitor JSH-23 reversed the facilitatory effect of USP43 knockdown on inflammatory cytokines. Mechanistically, USP43 interacts with and deubiquitinates TRAF4, thereby inhibiting NF-κB signaling and reducing proinflammatory cytokine levels. Importantly, TRAF4 overexpression partially reversed the increase in LPS-mediated NF-κB activation caused by USP43 knockdown. Collectively, our findings highlight a novel role for USP43 in suppressing intestinal inflammation through the inhibition of TRAF4-mediated NF-κB activation. These results reveal a new mechanism involving the USP43/TRAF4 axis in the regulation of intestinal inflammation.

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