C6ORF120 promotes DSS-induced colitis by inhibiting autophagy through the PI3K/AKT/mTOR signaling.

Abstract

BACKGROUND: C6ORF120 is an N-glycosylated secretory protein with unknown functions, particularly in the context of inflammatory bowel disease (IBD). This study aimed to clarify the role of C6ORF120 in IBD and delineate the underlying molecular mechanisms. METHODS: A colitis model was established in C6orf120 knockout (C6orf120) mice using dextran sulfate sodium (DSS). At the cellular level, inflammatory injury was simulated in Caco-2 cells through lipopolysaccharide (LPS) stimulation. A comprehensive array of techniques, including Western blot, immunohistochemistry, ELISA, transcriptome sequencing, autophagy flux assays, and transmission electron microscopy (TEM), was employed to systematically assess the impact of C6ORF120 on intestinal inflammation, autophagy, and associated signaling pathways. RESULTS: The knockout of C6orf120 markedly mitigated the severity of DSS-induced colitis in the murine models, as indicated by a reduction in body weight loss, amelioration of colon shortening, decreased infiltration of inflammatory cells, and diminished serum concentrations of inflammatory cytokines such as TNF-α, IL-1β, and IL-6. Simultaneously, the deficiency of C6ORF120 augmented the autophagic activity as evidenced by an increased LC3-II/I ratio and reduced p62 protein levels. Mechanistic investigations have demonstrated that C6ORF120 inhibits autophagy by activating the PI3K/AKT/mTOR signaling pathway, thereby intensifying intestinal inflammation. CONCLUSION: C6ORF120 facilitates the progression of DSS-induced colitis by suppressing protective autophagy through the activation of the PI3K/AKT/mTOR pathway. This study has elucidated the pivotal role of C6ORF120 in the pathogenesis of colitis and suggests a potential novel target for therapeutic intervention of inflammatory bowel disease.