Degradación de SLC3A2 mediada por ubiquitina de FBXO6 impulsa la ferroptosis en la colitis ulcerosa: un descubrimiento de aprendizaje automático y SHAP

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.

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.

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.

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.