Scholarlink

Background <p>Ulcerative colitis (UC) is a chronic inflammatory disease characterized by mucosal immune activation and epithelial barrier breakdown. The pathogenic mechanisms underlying UC remain incompletely understood, and identifying key molecular drivers of disease onset and progression may provide new therapeutic opportunities.</p> Methods <p>A total of 1,446 samples were integrated to identify key genes through machine learning and SHAP analysis. Immune infiltration, cytokine activity, barrier gene expression, and clinical outcomes were analyzed. Functional and mechanistic validations were further performed in lipopolysaccharide (LPS)–stimulated HT29 cells.</p> Results <p><i>FBXO6</i>, <i>COL1A2</i>, and <i>NPY</i> emerged as robust diagnostic biomarkers that stratify UC patients into molecular subgroups with distinct inflammatory states and therapeutic responses. High <i>FBXO6</i> expression correlated with macrophage-driven inflammation, barrier disruption, and reduced responsiveness to biologics. Mechanistically, <i>FBXO6</i> directly bound <i>SLC3A2</i> and induced its degradation through K48-linked ubiquitination, thereby promoting ferroptosis and amplifying mucosal inflammation.</p> Conclusion <p>A previously unrecognized ubiquitin-mediated <i>FBXO6</i>-<i>SLC3A2</i> axis was identified as a critical driver of ferroptosis and epithelial barrier disruption in UC. Targeting <i>FBXO6</i> to preserve <i>SLC3A2</i> stability is proposed as a potential therapeutic strategy to restore epithelial integrity and improve treatment responsiveness in patients with UC.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

FBXO6 mediated ubiquitination of SLC3A2 drives ferroptosis in ulcerative colitis: a machine learning and SHAP discovery

  • 期刊论文

  • 发表日期：

    2026年2月26日

查看全文
  • Longfei Dai,
  • Chao Yu,
  • Ronglin Xu,
  • Ruomu Ge,
  • Liangliang Zhang,
  • Along Li,
  • Xinjian Xu,
  • Zhen Zhang

摘要

Background

Ulcerative colitis (UC) is a chronic inflammatory disease characterized by mucosal immune activation and epithelial barrier breakdown. The pathogenic mechanisms underlying UC remain incompletely understood, and identifying key molecular drivers of disease onset and progression may provide new therapeutic opportunities.

Methods

A total of 1,446 samples were integrated to identify key genes through machine learning and SHAP analysis. Immune infiltration, cytokine activity, barrier gene expression, and clinical outcomes were analyzed. Functional and mechanistic validations were further performed in lipopolysaccharide (LPS)–stimulated HT29 cells.

Results

FBXO6, COL1A2, and NPY emerged as robust diagnostic biomarkers that stratify UC patients into molecular subgroups with distinct inflammatory states and therapeutic responses. High FBXO6 expression correlated with macrophage-driven inflammation, barrier disruption, and reduced responsiveness to biologics. Mechanistically, FBXO6 directly bound SLC3A2 and induced its degradation through K48-linked ubiquitination, thereby promoting ferroptosis and amplifying mucosal inflammation.

Conclusion

A previously unrecognized ubiquitin-mediated FBXO6-SLC3A2 axis was identified as a critical driver of ferroptosis and epithelial barrier disruption in UC. Targeting FBXO6 to preserve SLC3A2 stability is proposed as a potential therapeutic strategy to restore epithelial integrity and improve treatment responsiveness in patients with UC.