Abstract

Liver fibrosis represents a critical pathological stage in chronic liver disease, characterized by excessive activation of hepatic stellate cells (HSCs) and dysregulated immune cell recruitment. Our previous studies demonstrated that overexpressing tyrosine kinase receptor B (TrkB) in HSCs inhibits their activation, thereby alleviating liver fibrosis. However, its functional significance in hepatocytes—the predominant parenchymal cells orchestrating liver homeostasis—remains poorly understood. Here, we investigate the mechanistic interplay between hepatocyte-specific TrkB signalling and liver fibrosis progression. Through integrated in vivo animal models and in vitro two- and three-dimensional systems, we demonstrate that elevated TrkB expression in hepatocytes reduces pro-fibrotic and inflammatory cytokines, attenuates HSC activation via paracrine signalling, and impairs monocyte-derived macrophage (MoMF) recruitment. Mechanistically, TrkB modulates the TGFβ/SMAD3 pathway by inhibiting p-SMAD3 nuclear translocation, thus suppressing FOS transcription. As a core component of the AP-1 transcription factor complex, FOS directly regulates CCL2, a pivotal chemokine for macrophage recruitment. Collectively, these results establish TrkB as a key regulatory node in the TGFβ/SMAD3/FOS/CCL2 signalling cascade, orchestrating macrophage-mediated fibrotic responses in the liver.