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

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

doi:10.1097/HEP.0000000000001458

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

Hepatology. 2025 Jul 4. doi: 10.1097/HEP.0000000000001458. Online ahead of print.

Authors

Yuecheng Guo^{1

2}, Qingqing Zhang^{1

2}, Binghang Li³, Weiming Dai^{4

5}, Bo Shen^{1

2}, Zhenyang Shen^{1

2}, Junjun Wang^{1

2}, Qichao Ge^{1

2}, Hanjing Zhangdi^{1

2}, Guangwen Chen^{1

2}, Qidi Zhang^{1

2}, Xiaobo Cai^{1

2}, Hui Dong^{1

2}, Guangjian Fan⁶, Lungen Lu^{1

2}, Fei Li^{1

2}

Affiliations

¹ Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
² Shanghai Key Laboratory of Pancreatic Diseases, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
³ Department of Gastroenterology, Huadong Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
⁴ Department of Gastroenterology, Peking University People's Hospital, Beijing, China.
⁵ Clinical Center of Immune-Mediated Digestive Diseases, Peking University People's Hospital, Beijing, China.
⁶ Precision Research Center for Refractory Diseases, Institute for Clinical Research, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.

PMID: 40622850
DOI: 10.1097/HEP.0000000000001458

Abstract

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. Blocking integrin αvβ1 receptors in HSCs suppressed their activation, which was induced by DRC-derived SPP1.

Conclusions: YB-1/GLI2 axis promotes DRC proliferation and SPP1 secretion, which facilitates HSC activation through integrin αvβ1 receptors. This study highlights the YB-1/GLI2/SPP1 signaling pathway as a potential target for therapeutic intervention in liver fibrosis.

Keywords: HCC; Y-box binding protein-1; ductular reaction; liver fibrosis; secreted phosphoprotein 1.