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YTHDC1 Is Essential for Postnatal Liver Development and Homeostasis.

Xinzhi Li1,2, Xueying Li1, Chunhong Liu1

  • 1HIT Center for Life Sciences, School of Life Science and Technology, State Key Laboratory of Matter Behaviors in Space Environment, Frontier Science Center for Interaction between Space Environment and Matter, Zhengzhou Research Institute, Harbin Institute of Technology, Harbin, 150001, China.

Advanced Science (Weinheim, Baden-Wurttemberg, Germany)
|June 19, 2025
PubMed
Summary

YTHDC1 is vital for hepatocyte maturation and liver health. Its absence causes liver injury and disease, highlighting its role in maintaining liver homeostasis.

Keywords:
FOXA1FOXA2YTHDC1liverliver injurym6A modificationpostnatal development

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Area of Science:

  • Hepatology
  • Molecular Biology
  • Developmental Biology

Background:

  • Hepatocyte maturation is critical for liver function and occurs postnatally.
  • The molecular regulators of hepatocyte maturation are not fully understood.
  • YTHDC1 is a key protein involved in RNA modification.

Purpose of the Study:

  • To investigate the role of YTHDC1 in hepatocyte maturation and liver homeostasis.
  • To elucidate the molecular mechanisms by which YTHDC1 regulates hepatocyte function.

Main Methods:

  • Hepatocyte-specific deletion of Ythdc1 in mice.
  • Analysis of liver function, histology, and molecular markers.
  • Investigation of YTHDC1's interaction with Foxa1 and Foxa2 mRNA via m6A recognition.

Main Results:

  • YTHDC1 expression increases postnatally in the liver.
  • Hepatocyte-specific Ythdc1 deletion impairs maturation, causing liver injury, inflammation, fibrosis, and promoting nonalcoholic steatohepatitis and hepatocellular carcinoma.
  • YTHDC1 enhances FOXA1 and FOXA2 expression posttranscriptionally by binding to their m6A-modified mRNA.

Conclusions:

  • YTHDC1 is a crucial positive regulator of postnatal hepatocyte maturation and liver homeostasis.
  • YTHDC1-mediated regulation of FOXA1 and FOXA2 is essential for preventing liver pathologies.
  • YTHDC1 acts through m6A recognition to promote the expression of key transcription factors, thereby controlling hepatocyte maturation.