Biliary YB-1/GLI2 axis facilitates ductular reaction and promotes HSC activation via SPP1/integrin αvβ1 signaling during liver fibrogenesis

作者：Yuecheng Guo, Qingqing Zhang, Binghang Li, Weiming Dai, Bo Shen, Zhenyang Shen, Junjun Wang, Qichao Ge, Hanjing Zhangdi, Guangwen Chen, Qidi Zhang, Xiaobo Cai, Hui Dong, Guangjian Fan, Lungen Lu, Fei Li · 发表于：Hepatology · 年份：2025 · DOI：10.1097/hep.0000000000001458 · 被引用次数：3 · 研究领域：RNA Research and Splicing、Hippo pathway signaling and YAP/TAZ、interferon and immune responses

BACKGROUND AND AIMS: Emerging evidence suggests that ductular reactive cells (DRCs)-mediated ductular reaction (DR) accelerates the activation of HSCs and contributes to liver fibrogenesis. Previous studies implicated Y-box binding protein 1 (YB-1) in promoting DRC expansion. This study aims to investigate the mechanisms underlying YB-1-mediated DR and its role in HSC activation. APPROACH AND RESULTS: YB-1 was highly expressed in DRCs in human injured livers. CK19 CreERT mice were crossed with YB-1 flox/flox mice to generate DRC-specific YB-1 knockout mice. DRC-specific YB-1 deletion attenuated DR and liver injury induced by 3,5-methoxycarbonyl-1,4-dihydrocollidine (DDC) feeding and carbon tetrachloride (CCl 4 ) treatment. Transcriptomic analyses, along with chromatin immunoprecipitation and luciferase assays, revealed that YB-1 transcriptionally regulated GLI2 and promoted DRC proliferation. Pharmacological inhibition of GLI2 significantly attenuated DR and liver fibrosis in DDC and CCl 4 mouse models. The Transwell co-culture assay indicated that YB-1/GLI2 axis in DRCs drives HSC activation. Liquid chromatography-mass spectrometry combined with bioinformatic analyses identified secreted phosphoprotein 1 (SPP1) as the key molecule linking YB-1/GLI2-mediated DR to HSC activation. SPP1 was highly expressed in human injured livers and interacted with integrins. DRC-specific YB-1 knockout decreased the co-localization of SPP1 and integrin αvβ1 receptors in mouse fibrotic livers....