Qianqian Zheng, Yanli Cao, Xuefeng Jiang, Xiao Wang, Xiaonan Wang, Yan He, Wenmeng Ma, Hao Wu, Yuxuan Jiang, TONGXIN WANG, Xinyu Li, Chen Ding, Xun Sun
CHI3L1 level is independently associated with advanced liver fibrosis and shows good diagnostic performance for both significant and advanced liver fibrosis. It is a valuable non-invasive biomarker to supplement existing fibrosis assessment strategies, pending validation across individual AILDs subtypes.
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease driven by chronic inflammation and fibrosis, yet the immune mechanisms behind it remain unclear. We identify chitinase 3-like 1 (CHI3L1) as a key mediator linking immune activation to fibrotic remodeling in MASH. Across hepatocyte-macrophage coculture and recombinant interleukin-17A (IL-17A) stimulation assays, we delineate a hepatocyte-associated IL-17A signal that augments macrophage CHI3L1 expression via c-Jun N-terminal kinase (JNK)/c-Jun signaling. CHI3L1 then binds to IL-13Rα2 on hepatic stellate cells (HSCs), triggering a p38 mitogen-activated protein kinase (MAPK)/activating transcription factor 3 (ATF3) cascade that induces lipocalin-2 (LCN2), promoting HSC activation and fibrosis. Using cell-specific knockout models, we show that deleting Chi3l1 in macrophages or Il13ra2 in HSCs markedly reduces liver inflammation and fibrosis. Furthermore, CHI3L1-neutralizing antibodies disrupt this circuit and significantly improve disease outcomes in mice. These findings uncover a complete IL-17A–CHI3L1–IL-13Rα2–LCN2 signaling network, positioning CHI3L1 as both a mechanistic effector and a promising therapeutic target in MASH-fibrosis.