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  3. Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1

Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1

  • Redox Biol. 2025 Mar 14:82:103597. doi: 10.1016/j.redox.2025.103597.
Gang She 1,  Xia-Xia Hai 2,  Li-Ye Jia 3,  Yong-Jian Zhang 4,  Yu-Jie Ren 5,  Zheng-Da Pang 2,  Lin-Hong Wu 2,  Meng-Zhuan Han 2,  Yu Zhang 2,  Jing-Jing Li 2,  Ru-Yue Bai 2,  Bao-Chang Lai 6,  Yi-Yi Yang 2,  Junichi Sadoshima 7,  Xiao-Jun Du 8,  Xiu-Ling Deng 9,  Yi Zhang 10
Affiliations

Affiliations

  • 1 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China; Department of Cardiology, The Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, 710061, Shaanxi, China.
  • 2 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China.
  • 3 School of Nursing and Rehabilitation, Xi'an Medical University, 1 Xinwang Road, Xi'an, 710021, Shaanxi, China.
  • 4 Department of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 88 Zhuque Street, Xi'an, 710061, Shaanxi, China.
  • 5 Department of Pathology, Xi'an People's Hospital (Xian Fourth Hospital), Affiliated to Xi'an Jiaotong University Health Science Center, 21 Jiefang Road, Xi'an, 710005, Shaanxi, China.
  • 6 Cardiovascular Research Centre, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China.
  • 7 Department of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, New Jersey, United States of America.
  • 8 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China; Baker Heart and Diabetes Institute, 75 Commercial Road, Melbourne, Victoria, 3004, Australia.
  • 9 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China. Electronic address: dengxl@mail.xjtu.edu.cn.
  • 10 Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, China. Electronic address: zhangyixjtu@xjtu.edu.cn.
PMID: 40107016 DOI: 10.1016/j.redox.2025.103597
Abstract

Cardiomyocyte loss by regulated death modes, like Apoptosis and Ferroptosis, has been implicated in the development of dilated cardiomyopathy (DCM). It remains unclear whether cardiomyocyte Ferroptosis occurs as a consequence of Hippo pathway activation. Using a mouse model of DCM by overexpression of Mst1 transgene (Mst1-TG) leading to Hippo pathway activation, we showed that cardiomyocyte Ferroptosis was evident by transcriptomic profiles, elevated mitochondrial Fe2+ content, increased levels of lipid peroxidation and obvious mitochondrial damage. Transcriptome revealed significant alterations of genes participating in iron metabolism and lipid peroxidation. Treatment of Mst1-TG mice with the Ferroptosis inhibitor ferrostatin-1 reduced cardiomyocyte Ferroptosis and improved cardiac function. Using heart samples from human patients with DCM, we also found significant cardiomyocyte loss and lipid peroxidation. In cultured cardiomyocytes, Ferroptosis was induced by treatment with erastin or YAP Inhibitor verteporfin, and cell Ferroptosis under these conditions was largely prevented by either iron chelation or Mst1 gene knockdown. In a strain of transgenic mice with cardiomyocyte inactivation of Mst1 (dnMst1-TG), erastin-induced Ferroptosis and cardiac dysfunction, seen in control mice, were mitigated. Mechanistically, nuclear YAP and YY1 were shown to interact and bind to the Nfs1 promoter, thus mediating downregulation of Nfs1 (encoding cysteine desulfurase). Subsequent inhibition of iron-sulfur cluster (ISC) biosynthesis promoted cardiomyocyte Ferroptosis and DCM phenotype. Restoration of Nfs1 expression was achieved by treatment of Mst1-TG mice with AAV9-Nfs1 virus, which alleviated Ferroptosis, mitochondrial damage and DCM phenotype. In conclusion, in the DCM model with Hippo pathway activation, our findings unravel that NFS1 downregulation occurs and leads to insufficient ISC biosynthesis and cardiomyocyte Ferroptosis. Our findings implicate that restoration of cardiomyocyte NFS1 level may represent a new therapeutic strategy for DCM.

Keywords

Dilated cardiomyopathy; Ferroptosis; Hippo pathway; Iron-sulfur cluster; NFS1.

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