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<p>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.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月16日

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  • Li Zhou,
  • Dongliang Li,
  • Yan Lv,
  • Jian Fang,
  • Yue Liu,
  • Zhencheng Zhu,
  • Xin Tang,
  • Bo Zhang,
  • Chenjiang Qu,
  • Qiuhua Liu

摘要

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.