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N6-methyladenosine-modified circIRF2, identified by YTHDF2, suppresses liver fibrosis via facilitating FOXO3 nuclear

Xin Chen1, Sai Zhu2, Hai-Di Li1

  • 1Inflammation and Immune Mediated Diseases Laboratory of Anhui Province, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei 230032, China; The Key Laboratory of Anti-inflammatory and Immune Medicines, Anhui Medical University, Ministry of Education, Hefei 230032, China; Institute for Liver Diseases of Anhui Medical University, ILD-AMU, Anhui Medical University, Hefei 230032, China.

International Journal of Biological Macromolecules
|July 19, 2023
PubMed

Insights

Circular RNA IRF2 (circIRF2) is reduced in liver fibrosis. Restoring circIRF2 alleviates fibrosis by regulating miR-29b-1-5p and FOXO3, suggesting circIRF2 as a therapeutic target.

Area of Science:

  • Molecular Biology
  • Hepatology
  • Epigenetics

Background:

  • Circular RNAs (circRNAs) play roles in liver fibrosis through unknown mechanisms.
  • N6-methyladenosine (m6A) modification influences gene expression but its role in circRNA regulation in fibrosis is unclear.

Purpose of the Study:

  • To investigate the role of circIRF2 in liver fibrosis.
  • To elucidate the molecular mechanisms underlying circIRF2 regulation and function in liver fibrosis.
  • To assess circIRF2 as a potential biomarker or therapeutic target for liver fibrosis.

Main Methods:

  • circRNA sequencing to identify circIRF2.
  • In vivo gain/loss-of-function studies in mice to assess circIRF2's role in fibrogenesis and resolution.
  • Mechanistic studies involving m6A reader YTHDF2, miRNA-mRNA interactions (miR-29b-1-5p, FOXO3), and protein localization.
  • Microarray analysis to identify circIRF2-regulated miRNAs.
  • Clinical sample analysis to compare circIRF2 levels in patients with liver fibrosis and healthy individuals.

Main Results:

  • circIRF2 levels decreased during liver fibrogenesis and were restored during resolution.
  • Ectopic circIRF2 expression attenuated liver fibrosis and hepatic stellate cell (HSC) activation.
  • circIRF2 downregulation impaired liver injury repair and inflammation resolution.
  • YTHDF2 recognized m6A-modified circIRF2, reducing its stability.
  • circIRF2 sponged miR-29b-1-5p, relieving its inhibition on FOXO3 and promoting FOXO3 nuclear translocation.
  • circIRF2 downregulation was observed in liver fibrosis patients.

Conclusions:

  • circIRF2 is a crucial regulator in liver fibrosis progression and resolution.
  • m6A modification and YTHDF2 contribute to decreased circIRF2 stability in liver fibrosis.
  • The circIRF2/miR-29b-1-5p/FOXO3 axis is a key pathway in liver fibrosis.
  • circIRF2 represents a potential prognostic marker and therapeutic target for liver fibrosis.
Keywords:
FOXO3Liver fibrosisYTHDF2circIRF2circRNAsm(6)A

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