2. Academic Validation
  3. Suppression of dual-specificity phosphatase 6 protects against liver fibrosis via targeting CYP2E1-mediated ferroptosis

Suppression of dual-specificity phosphatase 6 protects against liver fibrosis via targeting CYP2E1-mediated ferroptosis

  • Int J Biol Macromol. 2025 Dec 27;339(Pt 1):149856. doi: 10.1016/j.ijbiomac.2025.149856.
Can Jiang 1,  Xiaoli Tang 2,  Ziyang Xu 3,  Miao Wang 1,  Zhonghui Wu 2,  Aizhong Wang 1,  Jichao Qin 4,  Zhengyun Zhang 5
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China.
  • 2 Department of Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China.
  • 3 School of Medicine, Tongji University, China; Department of Gastrointestinal Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, China.
  • 4 Department of Gastrointestinal Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, China. Electronic address: [email protected].
  • 5 Department of Surgery, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, China; Department of Gastrointestinal Surgery, the First Affiliated Hospital, Zhejiang University School of Medicine, China. Electronic address: [email protected].
PMID: 41461229 DOI: 10.1016/j.ijbiomac.2025.149856
Abstract

DUSP6, a dual-specificity Phosphatase, has become a focal point in understanding the pathogenesis of various liver disorders. This study aims to investigate the role of DUSP6 in liver fibrosis and explore the underlying mechanism. Using a CCL4-induced mouse model, the consistent upregulation of DUSP6 expression was observed. Notably, when Dusp6 was knocked down, liver fibrosis showed significant improvement, revealing a protective effect intricately linked to the ERK pathway. This was accompanied by an increase in ferroptosis-related proteins SLC7A11 and GPX4, underscoring the role of Ferroptosis, an iron-dependent form of regulated cell death, in this process. Transcriptomic analysis further revealed a crucial downregulation of Cyp2e1 following Dusp6 knockdown. In vitro, DUSP6 knockdown not only promoted ERK phosphorylation but also suppressed CYP2E1 expression, enhancing cell proliferation, bolstering hepatocyte resistance to Ferroptosis, and alleviating hepatocyte injury. Importantly, inhibiting CYP2E1 in mouse models of liver fibrosis effectively slowed the progression. These findings illuminate a critical regulatory mechanism that DUSP6 regulates liver fibrosis via targeting Ferroptosis, offering new a direction for therapeutic strategies in liver disease.

Keywords

DUSP6; Ferroptosis; Liver fibrosis.

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