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

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.