2. Academic Validation
  3. p16Ink4a-Positive Hepatocytes Drive Liver Fibrosis Through Activation of LIFR Family Pathway

p16Ink4a-Positive Hepatocytes Drive Liver Fibrosis Through Activation of LIFR Family Pathway

  • Adv Sci (Weinh). 2026 Jan 25:e10562. doi: 10.1002/advs.202510562.
Koji Nishikawa 1 2,  Teh-Wei Wang 1 3,  Satoshi Kawakami 1,  Shota Tanimoto 1,  Kiyoshi Yamaguchi 4,  Taketomo Kido 5,  Masamichi Kimura 2,  Tsunekazu Hishima 6,  Yuki T Okamura 1 3,  Satotaka Omori 7,  Takumi Iritani 3 8,  Toshikaze Chiba 3 9,  Takehiro Jimbo 3 9,  Michio Katano 3 8,  Kansuporn Kamataki 3 8,  Ryoichi Yokoyama 3 9,  Eigo Shimizu 10,  Kiminori Kimura 2,  Satoshi Yamzaki 11,  Seiya Imoto 10,  Yoichi Furukawa 4,  Atsushi Miyajima 5,  Yoshikazu Johmura 12,  Makoto Nakanishi 1
Affiliations

Affiliations

  • 1 Division of Cancer Cell Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 2 Department of Hepatology, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan.
  • 3 Project Division of Generative AI Utilization Aging Cells, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 4 Division of Clinical Genome Research, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 5 Laboratory of Cell Growth and Differentiation, Institute for Quantitative Biosciences, The University of Tokyo, Tokyo, Japan.
  • 6 Department of Pathology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
  • 7 Integrated Biosciences, Redwood City, California, USA.
  • 8 GMO Internet Group, Inc., Tokyo, Japan.
  • 9 GMO Research Activity Support & Technology, Inc., Tokyo, Japan.
  • 10 Division of Health Medical Intelligence, Human Genome Center, Center for Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 11 Division of Cell Regulation, Center of Experimental Medicine and Systems Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 12 Division of Cancer and Senescence Biology, Cancer Research Institute, Kanazawa University, Kakuma, Kanazawa, Japan.
PMID: 41580988 DOI: 10.1002/advs.202510562
Abstract

As organs undergo the process of aging, they exhibit signs of progressive fibrosis, a hallmark of aging that is observed in various organs, including the liver, kidneys, and lungs. Liver fibrosis is a particularly deleterious outcome of the healing processes that occur during the repair of chronic liver injury. It is widely accepted that the majority of these injuries are initially triggered by hepatocytes. Indeed, elderly patients have been shown to be more prone to developing liver fibrosis following hepatic injury. However, the mechanisms by which aging promotes fibrotic processes remain to be elucidated. The preceding observation, indicating a robust correlation between the severity of fibrosis in human cirrhotic patients and the population of hepatocytes expressing elevated levels of p16Ink4a (p16h), proposes that p16h hepatocytes might serve as initiators of fibrogenic processes in response to liver injury. In this study, we employed a CCl4-induced hepatitis model to promote a fibrogenic process and observed the accumulation of p16h hepatocytes in zone 3. These p16h cells manifest numerous senescent characteristics, and their accumulation has been strongly correlated with the severity of liver fibrosis. Selective elimination of p16h hepatocytes has been shown to ameliorate CCl4-induced liver fibrosis, presumably through the suppression of hepatic stellate cell activation. Single-cell transcriptomic analysis revealed that murine and human hepatocytes up-regulated Ctf1 or Lif, the ligands of the LIFR signaling pathway. The administration of LIFR ligands has been demonstrated to enhance the phosphorylation of STAT3, and the LIFR inhibitor rescued the fibrogenic phenotype in hepatic stellate cells induced by secreted factors from senescent hepatocytes. This finding offers potential therapeutic insights for the management of liver fibrosis.

Keywords

LIFR pathway; cellular senescence; liver fibrosis.

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  • Cat. No.
    Product Name
    Description
    Target
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  • HY-120142
    99.77%, LIFR Inhibitor