The Combined Effects of Circular RNA Methylation Promote Pulmonary Fibrosis

Sha Wang1,2,3,4, Wei Luo1,2,3,4, Jie Huang1,2

  • 1Department of Physiology, School of Medicine, Southeast University, Nanjing, Jiangsu, China.

Insights

N6-methyladenosine (m6A) modification of circular RNAs (circRNAs) plays a key role in silica-induced pulmonary fibrosis. METTL3-mediated m6A circRNAs synergistically promote fibroblast dysfunction, offering potential therapeutic targets for fibrosis.

Area of Science:

  • Epitranscriptomics
  • Molecular Biology
  • Pulmonary Medicine

Background:

  • N6-methyladenosine (m6A) is the most prevalent RNA modification, primarily on mRNA.
  • The role of m6A-modified circular RNAs (circRNAs) in pulmonary fibrosis is not well understood.

Purpose of the Study:

  • To investigate the involvement of m6A-modified circRNAs in silica-induced pulmonary fibrosis.
  • To elucidate the underlying molecular mechanisms and identify potential therapeutic targets.

Main Methods:

  • Utilized an m6A-circRNA epitranscriptomic chip to identify candidate circRNAs.
  • Conducted mechanistic studies to explore the role of METTL3 and specific circRNAs (hsa_circ_0000672, hsa_circ_0005654) in fibroblast function.
  • Investigated the interaction with eIF4A3.

Main Results:

  • Identified hsa_circ_0000672 and hsa_circ_0005654 as key players in SiO2-induced pulmonary fibrosis.
  • Demonstrated that m6A modification of these circRNAs synergistically impairs fibroblast function via eIF4A3.
  • Revealed that METTL3 mediates circRNA m6A modification, promoting fibroblast activation, migration, and activity in silica-induced fibrosis.

Conclusions:

  • m6A methylation of circRNAs is a critical mediator of silica-induced pulmonary fibrosis.
  • METTL3-driven m6A circRNA modification contributes to fibroblast dysfunction.
  • These findings highlight circRNA m6A modification as a potential therapeutic strategy for treating fibrotic diseases.

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