CDKN1A and EGR1 are key genes for endoplasmic reticulum stress-induced ferroptosis in MASH.

Journal: Free radical biology & medicine
Published Date: May 23, 2025

Abstract

Metabolic dysfunction-associated steatohepatitis (MASH) is a complex liver disease whose pathogenesis involving endoplasmic reticulum (ER) stress and ferroptosis. However, key regulatory genes remain poorly understood, hindering the development of effective therapeutic targets. This study aims to identify genes linked to ER stress and ferroptosis through bioinformatics and experimental validation, providing insights into MASH pathogenesis and potential therapeutic strategies. We first identified ER stress and ferroptosis as key processes in MASH through differential analysis and functional enrichment. This was subsequently validated in a high-fat diet (HFD)-induced MASH model in ApoE mice, where ER stress and ferroptosis were confirmed to occur in the liver tissue of MASH mice. Additionally, daily intraperitoneal injection of the ferroptosis inhibitor ferrostatin-1 (Fer-1) alleviated MASH progression. In vitro, Fer-1 mitigated inflammation, lipid accumulation, and fibrosis in free fatty acid (FFA)-treated HepG2 cells. To identify key genes, we employed bioinformatics analysis and machine learning approaches, which led to the identification of cyclin dependent kinase inhibitor 1A (CDKN1A) and early growth response 1 (EGR1) as feature genes associated with MASH-related ER stress and ferroptosis. Increased expression of CDKN1A and decreased expression of EGR1 were observed in the liver tissue of MASH mice and FFA-treated HepG2 cells. Furthermore, in CDKN1A overexpression and EGR1 silencing cell models, treatment with the ER stress inhibitor 4-Phenylbutyric acid improved the ferroptosis. In summary, all results indicate that CDKN1A and EGR1 are key genes driving ER stress-induced ferroptosis in MASH. Our findings not only provide new evidence for the pathogenesis of MASH but also highlight novel therapeutic targets for intervention.

Authors

  • Qian Xu
    College of Information Science and Engineering, Hunan Normal University, Changsha, P.R. China.
  • Yanyu Chen
    ProNet Biotech Co. ltd, Nanjing 210033, China.
  • Huayu Zhang
    Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Leiden University Medical Center, Albinusdreef, 22333 ZA Leiden, The Netherlands.
  • Kun Zhou
    School of Mathematics Science, Peking University, Beijing, China.
  • Yuanqin Zhao
    Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan Province, 421001, PR China.
  • Wei Deng
    Department of Neurobiology, Affiliated Mental Health Center & Hangzhou Seventh People's Hospital, Zhejiang University School of Medicine, Hangzhou, China. dengw@zju.edu.cn.
  • Zhaoyue Wang
    School of Electronics and Communication Engineering, Guangzhou University, Guangzhou 510006, China.
  • Liyuan Guo
    Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan Province, 421001, PR China.
  • Huiting Liu
  • Zhong Ren
    Key Laboratory of Optic-Electronic and Communication, Jiangxi Science and Technology Normal University, Nanchang, China.
  • Lushan Liu
    Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan Province, 421001, PR China.
  • Zhihan Tang
    Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan Province, 421001, PR China. Electronic address: Tangzhihan98@163.com.
  • Zhisheng Jiang
    Institute of Cardiovascular Disease, Key Laboratory for Arteriosclerology of Hunan Province, Hunan International Scientific and Technological Cooperation Base of Arteriosclerotic Disease, Hengyang Medical School, University of South China, Hengyang, Hunan Province, 421001, PR China. Electronic address: zsjiang2016@163.com.

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