CLEC4G deficiency aggravates cholestatic liver fibrosis through impaired angiocrine signaling

CLEC4G is a C-type lectin receptor predominantly expressed in liver sinusoidal endothelial cells (LSECs), with its expression markedly downregulated in cirrhotic livers. However, its specific role in cholestatic liver injury and fibrosis remains largely unexplored. Here we show that CLEC4G expression is reduced in cholestatic livers from children with biliary atresia (BA) and in bile duct ligation (BDL) -treated mice. Clec4g knockout (Clec4g−/−) mice exhibit LSEC capillarization, enhanced macrophage infiltration, and disrupted hepatic metabolic homeostasis. Genetic deletion of Clec4g aggravates BDL or a 3, 5-diethoxycarbonyl‑1, 4‑dihydrocollidine (DDC) diet-induced liver injury and fibrosis, and these effects can be attenuated by administration of recombinant R-spondin 1 (RSPO1). Mechanistically, KLF4 activation promotes chromatin accessibility and transcriptional activity to upregulate RSPO1 expression. Collectively, these findings demonstrate that CLEC4G protects against cholestatic liver injury and fibrosis by preserving LSEC integrity and sustaining the KLF4–RSPO1 angiocrine signaling axis. Thus, therapeutic targeting of CLEC4G may represent a promising strategy for the treatment of cholestatic liver diseases. The role of CLEC4G in cholestatic liver fibrosis is investigated using knockout mice and clinical samples. CLEC4G deficiency aggravates fibrosis by disrupting LSEC integrity and the KLF4–RSPO1 angiocrine axis, revealing a protective target for therapy.