LSEC-derived CXCL9 orchestrates immune recruitment and hepatocyte reprogramming in liver fibrosis

<p indent="0mm">Chronic liver injury involves complex intercellular communication, yet the contribution of non-classical immune cell populations remains incompletely understood. Here, we identify liver sinusoidal endothelial cell (LSEC)-derived CXCL9 as a pivotal regulator of hepatocyte reprogramming and fibrogenesis in chronic liver injury. Through the integration of bulk transcriptomic profiling, single-cell RNA sequencing, and <italic>in vitro</italic> hepatocyte assays, we demonstrate that CXCL9 is robustly upregulated in LSECs, rather than Kupffer cells or hepatic stellate cells, following toxic liver injury. KEGG enrichment analysis reveals significant activation of the chemokine signaling pathway (NES=1.75, <italic>P</italic>.adj=1.9×10^-4), and functional experiments shows that exogenous CXCL9 potently induces both regenerative gene (<italic>Hbegf)</italic> and pro-inflammatory gene expressions (<italic>Ccl2</italic>, <italic>Cxcl2</italic>, <italic>Il6</italic>, and <italic>Tnf</italic>) in primary hepatocytes (<italic>P&lt;</italic>0.01). Gain- and loss-of-function co-culture models further confirm that LSEC-derived CXCL9 is both necessary and sufficient for hepatocyte inflammatory activation and regenerative responses, predominantly via CXCR3 signaling. These findings reveal an underappreciated LSEC-CXCL9-CXCR3 axis as a driver of maladaptive parenchymal reprogramming and fibrogenesis, expanding the paradigm of hepatic chemokine biology and highlighting a novel therapeutic target for chronic liver disease.