CHI3L1 promotes macrophage pyroptosis in ulcerative colitis via the BCAT1/NF-κB axis.

Abstract

BACKGROUND: Ulcerative colitis (UC) is a chronic inflammatory bowel disease marked by intestinal epithelial damage. Although pyroptosis is implicated in the pathogenesis of UC, the key regulators of this process remain unclear. Chitinase-3-like protein 1 (CHI3L1) is upregulated in multiple inflammatory conditions and has been proposed as a fecal biomarker for endoscopic activity in inflammatory bowel disease (IBD). This study investigates the role of CHI3L1 in regulating macrophage pyroptosis in UC. METHODS: We analyzed CHI3L1 expression in UC patient colon tissues using GEO datasets and immunohistochemistry. Functional effects of CHI3L1 were examined through genetic silencing and pharmacological inhibition in THP-1 macrophages and a dextran sulfate sodium (DSS)-induced murine colitis model. RNA sequencing was performed to identify downstream factors. Mechanisms were further validated via NF-κB pathway activation assays. RESULTS: CHI3L1 was significantly upregulated in UC patients and strongly correlated with NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome expression. Both CHI3L1 knockdown and inhibitor treatment attenuated pyroptosis in vitro and ameliorated colitis in mice. RNA-seq revealed branched-chain amino acid transaminase 1 (BCAT1) as a key downstream target of the pathway. CHI3L1 promoted pyroptosis via BCAT1-mediated activation of NF-κB signaling, and exogenous NF-κB activation reversed the protective effects of CHI3L1 inhibition. CONCLUSION: This study demonstrates that CHI3L1 promotes macrophage pyroptosis in UC via the BCAT1/NF-κB axis, highlighting its potential as a therapeutic target for ulcerative colitis.