Objective: Ulcerative colitis (UC) is a chronic colitis with unknown etiology. Circular RNA (circRNA) has shown regulatory effect in many diseases, but the role of circRNA in UC is barely known. This study uncovers the function and regulatory mechanism of circRNA HECTD1 (circHECTD1) in UC.Methods: Colonic mucosal tissues of 60 patients with active UC and 30 healthy controls were collected for H&E staining. Lipopolysaccharide (LPS) and dextran sulfate sodium (DSS) were used to induce inflammation and UC in Caco-2 cells and C57BL/6 mice where modification of circHECTD1, miR-182–5p and/or human antigen R (HuR) took place. The Caco-2 cells and the colon tissues of DSS-treated mice were collected for analysis of the expression levels of inflammatory cytokines, NLRP3 inflammasome, and autophagy-related proteins. The interactions among circHECTD1, miR-182–5p, and HuR were verified.Results: The colonic mucosal tissues of UC patients showed impaired autophagy and decreased expressions of circHECTD1 and HuR. Overexpression of circHECTD1 or HuR or inhibition of miR-182–5p suppressed inflammation and promoted autophagy of LPS-induced Caco-2 cells. The expression of HuR was promoted by circHECTD1 via miR-182–5p in Caco-2 cells. Overexpression of circHECTD1 reduced colonic injuries and inflammation by promoting autophagy in DSS-treated mice.Conclusion: Overexpression of circHECTD1 alleviates UC by promoting HuR-dependent autophagy via miR-182–5p. This study highlights the therapeutic potential of circHECTD1 for UC and adds to the knowledge of circRNA in the pathogenesis of UC.

This research focused on novel molecular mechanisms underlying microRNA (miR)-182-5p in ulcerative colitis (UC). Colon tissues were obtained from UC patients, and dextrose sodium sulfate (DSS)-induced mouse and interleukin-1β (IL-1β)-induced Caco-2 cell models were generated. Then, miR-182-5p, SMARCA5, and the Wnt/β-catenin signaling pathway were altered in IL-1β-stimulated Caco-2 cells and DSS-treated mice to assess their function. MiR-182-5p and SMARCA5 were upregulated and DNMT3A, β-catenin, and Cyclin D1 were downregulated in UC patients, IL-1β-stimulated Caco-2 cells, and DSS-treated mice. Mechanistically, miR-182-5p targeted DNMT3A to upregulate SMARCA5, thus blocking the Wnt/β-catenin signaling pathway. Moreover, SMARCA5 silencing or Wnt/β-catenin signaling pathway activation repressed apoptosis and augmented proliferation and epithelial barrier function of IL-1β-stimulated Caco-2 cells. SMARCA5 silencing annulled the impacts of miR-182-5p overexpression on IL-1β-stimulated Caco-2 cells. SMARCA5 silencing or miR-182-5p inhibition ameliorated intestinal barrier dysfunction in DSS-treated mice. Collectively, miR-182-5p aggravates UC by inactivating the Wnt/β-catenin signaling pathway through DNMT3A-mediated SMARCA5 methylation.