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Epitranscriptomic Control of Vascular Smooth Muscle Cell Ferroptosis by WTAP in the Pathogenesis of Vascular

Yanwei Yin1, Fangmeng Lei1, Zihe Dang1

  • 1Department of Cardiology, Wuxi No.2 People's Hospital, Wuxi, China.

Antioxidants & Redox Signaling
|March 5, 2026
PubMed
Abstract

Insights

Wilms tumor suppressor gene WT1-associated protein (WTAP) regulates vascular smooth muscle cell (VSMC) ferroptosis via the GAS5/EZH2/IRF4/FTH1 pathway. This finding reveals a novel mechanism in vascular restenosis and offers a potential therapeutic target.

Area of Science:

  • Cardiovascular Biology
  • Epigenetics
  • Cell Death Mechanisms

Background:

  • Vascular restenosis is a significant complication post-intervention, characterized by vascular smooth muscle cell (VSMC) proliferation and phenotypic changes.
  • Ferroptosis, a form of regulated cell death, contributes to VSMC dysfunction and vascular remodeling, but its epitranscriptomic regulation is not well understood.
  • N6-methyladenosine (m6A) RNA methylation, regulated by Wilms tumor gene WT1-associated protein (WTAP), plays a role in cellular processes, yet its function in VSMC ferroptosis remains unexplored.

Purpose of the Study:

  • To investigate the role of WTAP in regulating ferroptosis of VSMCs in the context of vascular restenosis.
  • To elucidate the molecular mechanisms by which WTAP controls VSMC ferroptosis and proliferation.

Main Methods:

  • Vascular restenosis was modeled using a balloon injury rat model and platelet-derived growth factor-BB (PDGF-BB)-stimulated VSMCs.
  • WTAP expression, global m6A levels, ferroptosis markers, reactive oxygen species (ROS), and lipid peroxidation were assessed.
  • Mechanistic studies focused on WTAP-mediated m6A modification of long non-coding RNA GAS5, its interaction with EZH2, and downstream effects on IRF4 and FTH1.

Main Results:

  • WTAP expression and m6A levels were reduced in restenotic tissues and cells.
  • WTAP overexpression stabilized GAS5, which inhibited EZH2-mediated repression of IRF4, leading to increased FTH1 and suppressed ferroptosis.
  • WTAP overexpression reduced ROS, lipid peroxidation, and VSMC proliferation, effects partially reversed by GAS5 or IRF4 knockdown.

Conclusions:

  • WTAP epitranscriptomically regulates VSMC ferroptosis through the GAS5/EZH2/IRF4/FTH1 axis.
  • This pathway represents a novel mechanism in vascular restenosis pathogenesis.
  • The WTAP-mediated regulation of ferroptosis presents a potential therapeutic target for vascular restenosis.
Keywords:
GAS5IRF4WTAPferroptosisvascular restenosis

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