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Background <p>The roles of Contactin-2 (CNTN2) and ferroptosis in heart failure and cardiac remodeling remain incompletely understood.</p> Results <p>CNTN2 was significantly upregulated in hypertrophic cardiomyopathy patients and heart failure mice. In cardiomyocyte specific CNTN2 conditional knockout (CNTN2 cKO) mice, transverse aortic constriction (TAC) induced markedly exacerbated heart failure, cardiac remodeling and ferroptosis compared to control mice. Ferroptosis inhibition substantially attenuated heart failure in CNTN2 cKO mice subjected to TAC, indicating that enhanced ferroptosis contributes to the detrimental effects of CNTN2 deficiency. RNA sequencing identified NUPR1, a ferroptosis repressor, as a downstream molecule of CNTN2. Mechanistically, CNTN2 activated the Lyn/eIF2α/ATF4 pathway to regulate NUPR1. CNTN2 overexpression attenuated Angiotensin II-induced cardiomyocyte ferroptosis and pathological remodeling, whereas these protective effects were abolished by Lyn or NUPR1 inhibitors. We further revealed CNTN2 and Lyn interacted with each other, and that CNTN2 interacted with Lyn through its 1-328aa domain. In vivo NUPR1 overexpression via AAV9 significantly mitigated TAC-induced heart failure and cardiac remodeling in CNTN2 cKO mice.</p> Conclusions <p>Our study demonstrates that CNTN2 protects against pressure overload induced heart failure and cardiac remodeling by regulating ferroptosis through the Lyn/eIF2α/ATF4/NUPR1 pathway, suggesting CNTN2 as a potential therapeutic target.</p>

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Contactin-2 mitigates heart failure and cardiac remodeling via regulation of NUPR1 and ferroptosis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月4日

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  • Yu-Dong Fei,
  • Zhi-Xing Wei,
  • Tai-Zhong Chen,
  • Liu-Hui Zhang,
  • Yi-Chao Zhang,
  • Jian-Wen Hou,
  • Qian Wang,
  • Xing-Xing Cai,
  • Mu Chen,
  • Yu-Li Yang,
  • Peng-Cheng Yao,
  • Zhen-Tao Fei,
  • Yangjinming Bai,
  • Ting-Ting Zhao,
  • Ji Yan,
  • Wei Li,
  • Mei Yang,
  • Rui Zhang,
  • Xiang-Dong Liu,
  • Ming-Zhe Zhao,
  • Xiao-Lei Xu,
  • Jian Sun,
  • Yue-Peng Wang,
  • Yi-Gang Li

摘要

Background

The roles of Contactin-2 (CNTN2) and ferroptosis in heart failure and cardiac remodeling remain incompletely understood.

Results

CNTN2 was significantly upregulated in hypertrophic cardiomyopathy patients and heart failure mice. In cardiomyocyte specific CNTN2 conditional knockout (CNTN2 cKO) mice, transverse aortic constriction (TAC) induced markedly exacerbated heart failure, cardiac remodeling and ferroptosis compared to control mice. Ferroptosis inhibition substantially attenuated heart failure in CNTN2 cKO mice subjected to TAC, indicating that enhanced ferroptosis contributes to the detrimental effects of CNTN2 deficiency. RNA sequencing identified NUPR1, a ferroptosis repressor, as a downstream molecule of CNTN2. Mechanistically, CNTN2 activated the Lyn/eIF2α/ATF4 pathway to regulate NUPR1. CNTN2 overexpression attenuated Angiotensin II-induced cardiomyocyte ferroptosis and pathological remodeling, whereas these protective effects were abolished by Lyn or NUPR1 inhibitors. We further revealed CNTN2 and Lyn interacted with each other, and that CNTN2 interacted with Lyn through its 1-328aa domain. In vivo NUPR1 overexpression via AAV9 significantly mitigated TAC-induced heart failure and cardiac remodeling in CNTN2 cKO mice.

Conclusions

Our study demonstrates that CNTN2 protects against pressure overload induced heart failure and cardiac remodeling by regulating ferroptosis through the Lyn/eIF2α/ATF4/NUPR1 pathway, suggesting CNTN2 as a potential therapeutic target.