Hepatocyte DDIT4 aggravates MASH progression through GPX4-mediated ferroptosis

  • Metabolism. 2026 Jul:180:156622. doi: 10.1016/j.metabol.2026.156622.
Huiying Wang  1 ,  Wen-Yue Liu  2 ,  Feng Zhang  3 ,  Wei Chen  3 ,  Jinying Hu  3 ,  Ruitang Cheng  3 ,  Zhinan Chen  3 ,  Dan Wu  3 ,  Lijun Xie  3 ,  Yongguang Tao  4 ,  Ming-Hua Zheng  5 ,  Fang Hu  6
Affiliations
  • 1. National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, the Second Xiangya Hospital of Central South University, Changsha, 410011, China; Innovation Center, Tonghua Dongbao Pharmaceutical Co., Ltd., Longemont International Building, 1018 Changning Road, Changning District, 200042, Shanghai, China.
  • 2. Department of Endocrinology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000, China.
  • 3. National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, the Second Xiangya Hospital of Central South University, Changsha, 410011, China.
  • 4. Key Laboratory of Carcinogenesis and Cancer Invasion (Ministry of Education), NHC Key Laboratory of Carcinogenesis (Central South University), Cancer Research Institute and Xiangya School of Basic Medicine, Central South University, Changsha, 410078, Hunan, China.
  • 5. MAFLD Research Center, Department of Hepatology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; Key Laboratory of Diagnosis and Treatment for the Development of Chronic Liver Disease in Zhejiang Province, Wenzhou, China. Electronic address: [email protected].
  • 6. National Clinical Research Center for Endocrine and Metabolic Diseases, Key Laboratory of Diabetes Immunology (Central South University), Ministry of Education, and Department of Metabolism and Endocrinology, the Second Xiangya Hospital of Central South University, Changsha, 410011, China. Electronic address: [email protected].
PMID: 41997496 DOI: 10.1016/j.metabol.2026.156622
Abstract

Background & aims: Metabolic dysfunction-associated steatohepatitis (MASH) is a progressive liver disease with limited therapeutic options, and the role of Ferroptosis in its pathogenesis remains to be fully understood. In this study, we aimed to investigate the action of DNA damage-inducible transcript 4 (DDIT4) in the Ferroptosis and regulation of MASH progression.

Methods: The Gene Expression Omnibus database of MASH mice models and Ferroptosis database were used to identify crucial Ferroptosis related genes in MASH. Hepatic DDIT4 expression was detected in MASH patients, mouse models and hepatocytes. The functional role of DDIT4 was assessed in different diet-induced MASH mice models with hepatocyte-specific DDIT4 overexpression or knockout. RNA-sequencing and immunoprecipitation-mass spectrometry (IP-MS) were performed to determine DDIT4 interacting proteins. Molecular docking was used to explore the potential compound targeting DDIT4.

Results: We have discovered significantly elevated DDIT4 levels in mice and patients with MASH, which were positively correlated with MASH severity. Hepatocyte-specific over-expression of DDIT4 aggravated Ferroptosis and MASH progression, while DDIT4 deletion alleviated Ferroptosis and MASH progression. Mechanistically, DDIT4 decreased Glutathione Peroxidase 4 (GPX4) expression in an mTORC1 dependent manner. Additionally, DDIT4 interacted with cytosolic GPX4 and inhibited TOM22-mediated mitochondrial translocation, resulting in mitochondrial GPX4 reduction and Ferroptosis activation. Importantly, through molecular docking and surface plasmon resonance (SPR), we have identified quercetagetin, a natural flavonoid, as a potential DDIT4-targeting compound. Administration of quercetagetin alleviated hepatic steatosis, inflammation, and fibrosis in MASH mice.

Conclusions: Our study establishes the DDIT4-GPX4-ferroptosis axis as a new regulatory node in MASH progression and highlights DDIT4 as a potential therapeutic target for MASH.

Keywords
DDIT4; Ferroptosis; GPX4; MASH; Quercetagetin.
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