Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1
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...
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Elsevier
2025-05-01
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| Series: | Redox Biology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2213231725001107 |
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| author | Gang She Xia-Xia Hai Li-Ye Jia Yong-Jian Zhang Yu-Jie Ren Zheng-Da Pang Lin-Hong Wu Meng-Zhuan Han Yu Zhang Jing-Jing Li Ru-Yue Bai Bao-Chang Lai Yi-Yi Yang Junichi Sadoshima Xiao-Jun Du Xiu-Ling Deng Yi Zhang |
| author_facet | Gang She Xia-Xia Hai Li-Ye Jia Yong-Jian Zhang Yu-Jie Ren Zheng-Da Pang Lin-Hong Wu Meng-Zhuan Han Yu Zhang Jing-Jing Li Ru-Yue Bai Bao-Chang Lai Yi-Yi Yang Junichi Sadoshima Xiao-Jun Du Xiu-Ling Deng Yi Zhang |
| author_sort | Gang She |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-9017ddc478f84efdbcd5ac59bbab6e9c |
| institution | DOAJ |
| issn | 2213-2317 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Redox Biology |
| spelling | doaj-art-9017ddc478f84efdbcd5ac59bbab6e9c2025-08-20T03:14:52ZengElsevierRedox Biology2213-23172025-05-018210359710.1016/j.redox.2025.103597Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1Gang She0Xia-Xia Hai1Li-Ye Jia2Yong-Jian Zhang3Yu-Jie Ren4Zheng-Da Pang5Lin-Hong Wu6Meng-Zhuan Han7Yu Zhang8Jing-Jing Li9Ru-Yue Bai10Bao-Chang Lai11Yi-Yi Yang12Junichi Sadoshima13Xiao-Jun Du14Xiu-Ling Deng15Yi Zhang16Department 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, ChinaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, ChinaSchool of Nursing and Rehabilitation, Xi'an Medical University, 1 Xinwang Road, Xi'an, 710021, Shaanxi, ChinaDepartment of Cardiovascular Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, 88 Zhuque Street, Xi'an, 710061, Shaanxi, ChinaDepartment 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, ChinaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, ChinaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, ChinaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, ChinaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, ChinaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, ChinaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, ChinaCardiovascular Research Centre, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, ChinaDepartment of Physiology and Pathophysiology, School of Basic Medical Sciences, Xi'an Jiaotong University Health Science Center, 76 West Yanta Road, Xi'an, 710061, Shaanxi, ChinaDepartment of Cell Biology and Molecular Medicine, Rutgers New Jersey Medical School, New Jersey, United States of AmericaDepartment 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; Corresponding author. 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.xiao-jun.du@baker.edu.auDepartment 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; Corresponding author.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; Corresponding author.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.http://www.sciencedirect.com/science/article/pii/S2213231725001107Dilated cardiomyopathyHippo pathwayFerroptosisNFS1Iron-sulfur cluster |
| spellingShingle | Gang She Xia-Xia Hai Li-Ye Jia Yong-Jian Zhang Yu-Jie Ren Zheng-Da Pang Lin-Hong Wu Meng-Zhuan Han Yu Zhang Jing-Jing Li Ru-Yue Bai Bao-Chang Lai Yi-Yi Yang Junichi Sadoshima Xiao-Jun Du Xiu-Ling Deng Yi Zhang Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1 Redox Biology Dilated cardiomyopathy Hippo pathway Ferroptosis NFS1 Iron-sulfur cluster |
| title | Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1 |
| title_full | Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1 |
| title_fullStr | Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1 |
| title_full_unstemmed | Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1 |
| title_short | Hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating NFS1 |
| title_sort | hippo pathway activation mediates cardiomyocyte ferroptosis to promote dilated cardiomyopathy through downregulating nfs1 |
| topic | Dilated cardiomyopathy Hippo pathway Ferroptosis NFS1 Iron-sulfur cluster |
| url | http://www.sciencedirect.com/science/article/pii/S2213231725001107 |
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