2. Academic Validation
  3. CXCL13 suppresses liver regeneration through the negative regulation of HGF signaling

CXCL13 suppresses liver regeneration through the negative regulation of HGF signaling

  • Cell Death Dis. 2025 May 5;16(1):361. doi: 10.1038/s41419-025-07568-2.
Qun Zhao # 1 2,  Jingyi Wu # 1 2,  Mengyuan Feng # 1 2,  Anjie Zhang 1 2,  Liwei Fu 1 2,  Jinglin Chen 3,  Lian Li 3,  Fangzhou Li 2,  Tingting Li 2,  Shu Jin 1,  Shengbao Li 4,  Xianjun Yu 5 6
Affiliations

Affiliations

  • 1 Department of Gastroenterology, Taihe Hospital, School of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, China.
  • 2 Laboratory of Inflammation and Molecular Pharmacology, Biomedical Research Institute, Inflammation-Cancer Transformation and Wudang Chinese Medicine Research, Hubei Talent Introduction and Innovation Demonstration Base, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Hubei University of Medicine, Shiyan, China.
  • 3 Department of Clinical Laboratory, Renmin Hospital, Hubei University of Medicine, Shiyan, China.
  • 4 Department of Gastroenterology, Taihe Hospital, School of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, China. libao@taihehospital.com.
  • 5 Department of Gastroenterology, Taihe Hospital, School of Basic Medical Sciences, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei University of Medicine, Shiyan, China. xjyu@hbmu.edu.cn.
  • 6 Laboratory of Inflammation and Molecular Pharmacology, Biomedical Research Institute, Inflammation-Cancer Transformation and Wudang Chinese Medicine Research, Hubei Talent Introduction and Innovation Demonstration Base, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Hubei University of Medicine, Shiyan, China. xjyu@hbmu.edu.cn.
  • # Contributed equally.
PMID: 40325003 DOI: 10.1038/s41419-025-07568-2
Abstract

Insufficient liver regeneration increases the risk of postoperative liver failure following liver transplantation or partial hepatectomy (PHx). Numerous growth factors and cytokines are related to liver regeneration; however, the underlying mechanisms have not been fully elucidated. In this study, CXCL13 was identified as a key factor delaying liver regeneration after PHx. We observed that CXCL13 expression was upregulated in PHx mice and patients following liver resection. CXCL13 deficiency accelerated liver regeneration, whereas these effects were abolished by recombinant murine CXCL13 administration. Moreover, proteomics analyses indicated that HGF levels in the serum after PHx were significantly greater in Cxcl13-/- mice than in WT mice. Further analysis revealed that CXCL13 deficiency promoted liver regeneration via elevated HGF expression in reparative macrophages and subsequent activated the HGF/c-MET axis in hepatocytes. Additionally, deficiency of macrophage CXCR5, the receptor for CXCL13, augmented liver regeneration and elevated HGF expression after PHx. Mechanistically, CXCL13 inhibited HGF expression in reparative macrophages via CXCR5-mediated Akt/FoxO3a signaling. We further determined that noncanonical NF-κB signaling activation induced CXCL13 expression in hepatic macrophages. Importantly, treatment with CXCL13-neutralizing antibody effectively improved liver regeneration in mice PHx model. Overall, our findings revealed a novel function of CXCL13 in negatively regulating liver regeneration. The underlying mechanism involved CXCL13/CXCR5-mediated FoxO3a signaling, which downregulated HGF expression in reparative macrophages and subsequently attenuated hepatocyte proliferation through inactivating HGF/c-MET signaling. These data suggest that therapeutic targeting of the CXCL13 signaling axis might decrease the risk of postoperative liver failure.

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