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Investigation of Macrophage Polarization Using Bone Marrow Derived Macrophages
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Investigation of Macrophage Polarization Using Bone Marrow Derived Macrophages

Published on: June 23, 2013

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METTL3-dependent N6-methyladenosine modification on LGMN mRNA promotes macrophage ferroptosis and atherosclerosis

Yang He1, Kaisheng Jiang1, Junhong Sun2

  • 1Faculty of Forensic Medicine, Guangdong Province Translational Forensic Medicine Engineering Technology Research Center, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.

Journal of Molecular and Cellular Cardiology
|January 8, 2026
PubMed

Insights

N6-methyladenosine (m6A) modification and methyltransferase-like 3 (METTL3) promote atherosclerosis by inducing macrophage ferroptosis via legumain (LGMN). Inhibiting METTL3 or LGMN reduces plaque formation and ferroptosis in macrophages.

Area of Science:

  • Biochemistry and Molecular Biology
  • Immunology
  • Cardiovascular Research

Background:

  • N6-methyladenosine (m6A) modification is crucial in biological processes, but its role in macrophages and atherosclerosis (AS) ferroptosis is unknown.
  • Elevated m6A modification and methyltransferase-like 3 (METTL3) are found in AS arteries, with increased METTL3-positive macrophages in both mouse and human AS.
  • Macrophage function and ferroptosis are implicated in AS pathogenesis.

Purpose of the Study:

  • To investigate the role of m6A modification and METTL3 in macrophage-driven ferroptosis during atherosclerosis.
  • To identify downstream targets of METTL3 in AS pathogenesis.
  • To elucidate the mechanism linking METTL3, ferroptosis, and legumain (LGMN) in AS.

Main Methods:

  • Systemic and macrophage-specific METTL3 knockdown in mouse models of AS.
  • RNA-sequencing of bone marrow-derived macrophages (BMDM) after METTL3 knockdown.
  • Analysis of legumain (LGMN) expression in response to oxidized low-density lipoprotein (ox-LDL) and METTL3/LGMN manipulation in BMDM and AS mouse models.
  • Investigation of YTHDF1 binding to m6A-modified LGMN mRNA.

Main Results:

  • METTL3 inhibition or knockdown reduced AS plaque formation and macrophage infiltration.
  • METTL3 knockdown in BMDM enriched ferroptosis-associated genes.
  • LGMN expression was upregulated in AS arteries and ox-LDL-treated BMDM; LGMN knockdown attenuated ox-LDL-induced ferroptosis, lipid deposition, and inflammation in vitro and in vivo.
  • METTL3 knockdown suppressed LGMN upregulation, and LGMN overexpression rescued METTL3 knockdown effects.
  • YTHDF1 mediated the translation of m6A-modified LGMN mRNA.

Conclusions:

  • LGMN acts as a novel mediator linking METTL3-dependent m6A modification to macrophage ferroptosis in atherosclerosis.
  • Targeting the METTL3-LGMN axis in macrophages may offer a therapeutic strategy for AS.
  • m6A modification plays a significant role in regulating macrophage function and ferroptosis in the context of AS.
Keywords:
AtherosclerosisFerroptosisLGMNMETTL3Macrophagem6A

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