Targeting hepatocyte TrkB to mitigate liver fibrosis via modulating macrophage recruitment

Liver fibrosis is a critical stage in the progression of chronic liver disease, yet effective therapies remain scarce due to its complex pathophysiology. Excessive activation of hepatic stellate cells (HSCs) and increased recruitment of immune cells are key drivers of this process. Our previous studies demonstrated that overexpressing tyrosine kinase receptor B (TrkB) in HSCs can inhibit their activation, thereby alleviating liver fibrosis. Given that hepatocytes make up the majority of liver cells and play a pivotal role in the pathogenesis of liver fibrosis, targeting hepatocytes is a more practical approach than targeting HSCs for therapeutic intervention. This study aims to evaluate the therapeutic effect of targeting TrkB in hepatocytes on liver fibrosis and explore the underlying mechanisms. To this end, we employed various models, including in vivo animal models and in vitro two-dimensional and three-dimensional systems. Our findings indicate that TrkB overexpression in hepatocytes significantly reduces the expression of cytokines linked to inflammation and fibrosis, directly inhibiting HSC activation and decreasing the recruitment of monocyte-derived macrophages (MoMFs), ultimately mitigating liver fibrosis. Mechanistically, TrkB overexpression modulates the TGFB/SMAD3 pathway by preventing p-SMAD3 nuclear translocation, thereby suppressing FOS transcription. As a component of the dimeric transcription factor AP-1, FOS directly regulates the transcription and secretion of CCL2, a critical cytokine involved in macrophage recruitment. This study highlights TrkB as a promising therapeutic target for liver fibrosis by disrupting the TGFB/SMAD3/FOS/CCL2 axis and alleviating fibrosis through macrophage recruitment.