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IGF2BP3/HIF1A/YAP signaling plays a role in driving acute-on-chronic liver failure through activating hepatocyte

Ke Cheng1, Shu Liu1, Cai Li1

  • 1Department of Transplantation, The Third Xiangya Hospital, Central South University, China; Engineering and Technology Research Center for Transplantation Medicine of National Health Commission, China.

Cellular Signalling
|May 31, 2023
PubMed
Abstract

Insights

We uncovered that IGF2BP3/HIF1A/YAP signaling drives hepatocyte reprogramming, leading to liver injury in acute-on-chronic liver failure (ACLF). This finding offers potential therapeutic targets for ACLF treatment.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Genomics

Background:

  • Acute-on-chronic liver failure (ACLF) presents high prevalence and mortality.
  • Underlying mechanisms of ACLF are not fully understood, lacking effective treatments.
  • Novel molecular mechanisms and therapeutic targets for ACLF require identification.

Purpose of the Study:

  • To uncover novel molecular mechanisms driving ACLF.
  • To identify potential therapeutic targets for ACLF.
  • To investigate the role of IGF2BP3/HIF1A signaling in ACLF pathogenesis.

Main Methods:

  • Integrative analysis of transcriptomic datasets and bioinformatic analysis.
  • Validation of gene and protein expression in clinical samples using western blot and qPCR.
  • Investigation of N6-methyladenosine (m6A) RNA modification of HIF1A.
  • Functional validation of molecular mechanisms in cell lines (HepG2, Hep3B) using gene manipulation.

Main Results:

  • IGF2BP3 acts as an m6A reader for HIF1A mRNA, enhancing its stability and expression.
  • HIF1A activation promotes RhoA and suppresses YAP phosphorylation by inhibiting LATS1/2.
  • Non-phosphorylated YAP translocation into the nucleus induces a fetal liver program, causing hepatic injury in ACLF.

Conclusions:

  • A novel molecular mechanism involving IGF2BP3/HIF1A/YAP signaling in hepatocyte reprogramming and ACLF-induced hepatic injury is revealed.
  • The identified signaling pathway provides potential therapeutic targets for ACLF treatment.
Keywords:
Acute-on-chronic liver failure (ACLF)Hepatocyte reprogramming/fetal liver programmeHypoxia-inducible factor (HIF)Insulin-like growth factor-2 RNA-binding protein-3 (IGF2BP3)N6-methyladenosine (m6A) RNA modificationYes-associated protein (YAP)

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