Background: Ulcerative colitis (UC), a chronic subtype within the spectrum of inflammatory bowel diseases, involves repeated episodes of mucosal injury and impairment of the epithelial barrier. Despite evidence suggesting numerous signaling pathways in UC pathogenesis, the underlying molecular mechanisms remain elusive. Herein, we sought to uncover disease-related genes and investigate the role of β-site APP cleaving enzyme 2 (BACE2) in disease progression.

Methods: Differentially expressed genes were screened from the GSE53306 and GSE75214 datasets. BACE2 expression in a murine UC model was examined using quantitative real-time PCR (qRT‒PCR), Western blotting, and immunohistochemistry assays. Functional assays were performed in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages following BACE2 knockdown, including qRT‒PCR, Western blotting, enzyme-linked immunosorbent assay (ELISA), Cell Counting Kit-8 (CCK-8) viability assays, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining, and flow cytometry. The potential contribution of the MAP kinase phosphatase-1 (MKP1)/nuclear factor kappa-B (NF-κB)/NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) pathway was examined. Finally, the effects of BACE2 silencing and MKP1 inhibition on disease progression were evaluated in vivo using a mouse model with UC.

Results: Bioinformatic analysis identified BACE2 as one of the top upregulated genes in UC datasets. In vivo, UC mice exhibited a notable reduction in body mass, an increased disease activity index, a shortened colon length, and increased expression of BACE2 at both transcriptional and protein levels (p < 0.05). Histopathological analysis revealed severe epithelial damage and inflammatory cell infiltration, accompanied by enhanced BACE2 expression in colon tissues. In vitro, BACE2 knockdown reduced LPS-stimulated tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and IL-6 production (p < 0.05), improved cell viability (p < 0.05), and attenuated apoptosis (p < 0.05). Mechanistically, BACE2 silencing restored MKP1 expression (p < 0.05), suppressed NF-κB activation (p < 0.05), and inhibited NLRP3 inflammasome signaling (p < 0.05). In UC mice, BACE2 knockdown alleviated colonic inflammation, whereas MKP1 inhibition partially reversed these protective effects.

Conclusion: BACE2 is aberrantly upregulated in UC and exacerbates disease progression by downregulating MKP1 and activating the NF-κB/NLRP3 pathway. Targeting BACE2 may provide a novel approach to inflammatory bowel disease.