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

  • Life Sci. 2026 Jan 1:384:124108. doi: 10.1016/j.lfs.2025.124108.
Jie Feng  1 ,  Huan Zhang  1 ,  Mengxin Zhu  1 ,  Qinpei Zhang  1 ,  Haokun Rong  2 ,  Tongguo Shi  3 ,  Qinhua Xi  4
Affiliations
  • 1. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China.
  • 2. Department of Neurology, The First Affiliated Hospital of Soochow University, Suzhou, China.
  • 3. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Institute of Clinical Immunology, The First Affiliated Hospital of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Clinical Immunology, Soochow University, Suzhou, China. Electronic address: [email protected].
  • 4. Department of Gastroenterology, The First Affiliated Hospital of Soochow University, Suzhou, China. Electronic address: [email protected].
PMID: 41314595 DOI: 10.1016/j.lfs.2025.124108
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.

Keywords
BCAT1; CHI3L1; NF-κB; Pyroptosis; Ulcerative colitis.
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