Characterization of ferroptosis-triggered pyroptotic signaling in heart failure

Signal Transduct Target Ther. 2024 Sep 25;9(1):257. doi: 10.1038/s41392-024-01962-6.

Xukun Bi ^# ¹, Xiaotian Wu ^# ² ³, Jiaqi Chen ¹, Xiaoting Li ¹, Yangjun Lin ¹, Yingying Yu ², Xuexian Fang ⁴, Xihao Cheng ², Zhaoxian Cai ², Tingting Jin ¹, Shuxian Han ⁵ ⁶, Meihui Wang ¹, Peidong Han ⁵ ⁶, Junxia Min ⁷, Guosheng Fu ⁸, Fudi Wang ⁹ ¹⁰ ¹¹

Affiliations

1 Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China.
2 The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China.
3 The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China.
4 Department of Nutrition and Toxicology, School of Public Health, Hangzhou Normal University, Hangzhou, China.
5 Center for Genetic Medicine, The Fourth Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
6 Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, China.
7 The First Affiliated Hospital, Institute of Translational Medicine, Zhejiang University School of Medicine, Hangzhou, China. junxiamin@zju.edu.cn.
8 Key Laboratory of Cardiovascular Intervention and Regenerative Medicine of Zhejiang Province, Department of Cardiology, Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China. fugs@zju.edu.cn.
9 The Second Affiliated Hospital, School of Public Health, State Key Laboratory of Experimental Hematology, Zhejiang University School of Medicine, Hangzhou, China. fwang@zju.edu.cn.
10 School of Public Health, School of Basic Medical Sciences, The First Affiliated Hospital, Hengyang Medical School, University of South China, Hengyang, China. fwang@zju.edu.cn.
11 School of Public Health, School of Basic Medical Sciences, The First Affiliated Hospital, Xinxiang Medical University, Xinxiang, China. fwang@zju.edu.cn.
# Contributed equally.

PMID: 39327446 DOI: 10.1038/s41392-024-01962-6

Abstract

Pressure overload-induced cardiac hypertrophy is a common cause of heart failure (HF), and emerging evidence suggests that excessive oxidized lipids have a detrimental effect on cardiomyocytes. However, the key regulator of lipid toxicity in cardiomyocytes during this pathological process remains unknown. Here, we used lipidomics profiling and RNA-seq analysis and found that phosphatidylethanolamines (PEs) and Acsl4 expression are significantly increased in mice with transverse aortic constriction (TAC)-induced HF compared to sham-operated mice. In addition, we found that overexpressing Acsl4 in cardiomyocytes exacerbates pressure overload‒induced cardiac dysfunction via Ferroptosis. Notably, both pharmacological inhibition and genetic deletion of Acsl4 significantly reduced left ventricular chamber size and improved cardiac function in mice with TAC-induced HF. Moreover, silencing Acsl4 expression in cultured neonatal rat ventricular myocytes was sufficient to inhibit hypertrophic stimulus‒induced cell growth. Mechanistically, we found that Acsl4-dependent Ferroptosis activates the pyroptotic signaling pathway, which leads to increased production of the proinflammatory cytokine IL-1β, and neutralizing IL-1β improved cardiac function in Acsl4 transgenic mice following TAC. These results indicate that ACSL4 plays an essential role in the heart during pressure overload‒induced cardiac remodeling via ferroptosis-induced pyroptotic signaling. Together, these findings provide compelling evidence that targeting the ACSL4-ferroptosis-pyroptotic signaling cascade may provide a promising therapeutic strategy for preventing heart failure.

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MedChemExpress (MCE) 只为有资质的科研机构、医药企业基于科学研究或药证申报的用途提供医药研发服务，不为任何个人或者非科研性质的、非用于药证申报使用等其他用途提供服务。

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