Decoding the CHI3L1/IL-13Rα2 signaling nexus in MASH-fibrosis pathogenesis.

Abstract

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 <i>Chi3l1</i> in macrophages or <i>Il13ra2</i> 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.