Targeting TARDBP to Restore Colonic Barrier Integrity in Ulcerative Colitis via NFATC1 mRNA Destabilization.

Abstract

Background/aims: Ulcerative colitis (UC) is a chronic inflammatory bowel disease characterized by limited understanding of post-transcriptional mechanisms governing intestinal barrier integrity. This study investigated the role of NFATC1 in modulating barrier function during colitis and identified RNA-binding proteins regulating its expression.

Materials and methods: An experimental model of UC was established in mice using dextran sulfate sodium (DSS). Adeno-associated virus vectors were used for in vivo knockdown of NFATC1 or overexpression of TARDBP. Colonic pathology was evaluated by histologic analysis and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assays for apoptosis. Inflammatory cytokines, oxidative stress markers, and intestinal permeability were quantified using enzyme-linked immunosorbent assay (ELISA) and commercial kits. The expression levels of NFATC1, TARDBP, TLR4/p-p65, Zonula occludens-1 (ZO-1), and occludin were assessed by reverse transcription quantitative polymerase chain reaction (RT-qPCR), western blotting, and immunofluorescence staining. The molecular interaction between TARDBP and NFATC1 was investigated using coimmunoprecipitation, actinomycin D chase assays, and RNA immunoprecipitation.

Results: DSS administration impaired colonic barrier integrity in mice and was associated with increased NFATC1 and decreased TARDBP expression. Notably, NFATC1 knockdown or TARDBP overexpression independently ameliorated DSS-induced colonic barrier damage. In contrast, the protective effects of TARDBP overexpression were abrogated by simultaneous NFATC1 overexpression. Mechanistically, TARDBP directly bound to NFATC1 mRNA, thereby promoting its degradation and reducing its stability rather than interacting at the protein level.

Conclusion: This study identified a novel post-transcriptional regulatory mechanism by which TARDBP attenuates colonic inflammation through destabilization of NFATC1 mRNA. These findings highlight the TARDBP-NFATC1 axis as a potential therapeutic target for restoring intestinal barrier function in UC. Cite this article as: Jiang Y, Gao J, Huang Y, et al. Targeting TARDBP to restore colonic barrier integrity in ulcerative colitis via NFATC1 mRNA destabilization. Turk J Gastroenterol. 2026;37(8):869-886.