METTL3-m6A-Rubicon axis inhibits autophagy in nonalcoholic fatty liver disease

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Updated: Oct 19, 2025

A Primary Human Trophoblast Model to Study the Effect of Inflammation Associated with Maternal Obesity on Regulation of Autophagy in the Placenta
11:44

A Primary Human Trophoblast Model to Study the Effect of Inflammation Associated with Maternal Obesity on Regulation of Autophagy in the Placenta

Published on: September 27, 2017

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Zishan Peng1, Yingying Gong2, Xuejie Wang1

  • 1Department of Endocrinology, The First Affiliated Hospital, Sun Yat-sen University, No. 58, Zhongshan Road 2, Guangzhou 510080, China.

Molecular Therapy : the Journal of the American Society of Gene Therapy
|September 21, 2021
PubMed

Insights

N6-methyladenosine (m6A) modification increases in nonalcoholic fatty liver disease (NAFLD) due to METTL3 upregulation. This inhibits autophagy and lipid droplet clearance, highlighting a novel role for m6A in NAFLD pathogenesis.

Area of Science:

  • Molecular Biology
  • Hepatology
  • Epigenetics

Background:

  • N6-methyladenosine (m6A) mRNA modification is crucial in biological processes and disease.
  • The role of m6A in nonalcoholic fatty liver disease (NAFLD) autophagy is not well understood.

Purpose of the Study:

  • To investigate the role of m6A modification in NAFLD-related autophagy.
  • To elucidate the mechanism by which m6A affects lipid metabolism in NAFLD.

Main Methods:

  • Utilized NAFLD mouse models and free fatty acid (FFA)-treated hepatocytes.
  • Examined the expression and function of methyltransferase like 3 (METTL3) and YTH N6-methyladenosine RNA binding protein 1 (YTHDF1).
  • Analyzed m6A modification levels, autophagic flux, and lipid droplet clearance.

Main Results:

  • m6A modification and METTL3 expression were elevated in NAFLD models, driven by lipotoxicity.
  • METTL3 knockdown enhanced autophagic flux and lipid clearance; METTL3 overexpression inhibited these processes.
  • METTL3 and YTHDF1 stabilized Rubicon mRNA, which impaired autophagosome-lysosome fusion and lipid clearance.

Conclusions:

  • METTL3 and YTHDF1 play a critical role in regulating lipid metabolism through the autophagy pathway in NAFLD.
  • m6A mRNA methylation represents a novel regulatory mechanism in NAFLD pathogenesis.
  • Targeting the METTL3-YTHDF1-Rubicon axis may offer therapeutic strategies for NAFLD.
Keywords:
METTL3NAFLDYTHDF1autophagym(6)A modification

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