Decoding the CHI3L1/IL-13Ra2 Signaling Nexus in MASH-Fibrosis Pathogenesis
Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive hepatic disorder marked by chronic inflammation and fibrotic remodeling, yet its immunoregulatory underpinnings remain incompletely elucidated. Emerging evidence positions chitinase 3-like 1 (CHI3L1) as a pivotal pleiotropic mediator implicated in MASH-associated fibrogenesis, serving dual roles as both diagnostic biomarker and pathogenic effector. However, the precise regulatory network and mechanism of the CHI3L1 axis remain unknown. Our investigation unveils a previously unrecognized CHI3L1-driven immunofibrotic circuit that mediates macrophage-hepatic stellate cells (HSCs) crosstalk to promoting hepatic fibrosis. Mechanistically, MASH-inducing dietary conditions provoke hepatocyte-derived IL-17A production, triggering a cascade of events through JNK/c-Jun-mediated transcriptional activation of CHI3L1 in hepatic macrophages. This glycoprotein then engages its cognate receptor IL-13Ralpha2 on quiescent HSCs, initiating a p38/MAPK/ATF3-dependent signaling cascade that upregulates lipocalin-2 (LCN2)-a potent activator of HSC activation and fibrogenesis. Employing cell-specific knockout mouse models, we demonstrate that macrophage-specific Chi3l1 ablation or HSCs-targeted Il13ra2 deletion achieves profound attenuation of fibroinflammatory pathology, functionally validating this axis as a master regulatory switch in MASH progression. Therapeutically, pharmacological neutralization of CHI3L1 using monoclonal antibodies not only disrupted this pathogenic circuitry but also yielded remarkable clinical improvement in murine models, reducing both necroinflammatory activity and fibrotic burden. These findings crystallize a novel molecular paradigm for MASH pathogenesis while establishing CHI3L1 as a linchpin connecting metabolic dysfunction, immune activation, and extracellular matrix remodeling. The mechanistic insights gained position this signaling axis as a compelling therapeutic frontier for precision intervention in progressive steatohepatitis.