2. Academic Validation
  3. FGF2 Mediated USP42-PPARγ Axis Activation Ameliorates Liver Oxidative Damage and Promotes Regeneration

FGF2 Mediated USP42-PPARγ Axis Activation Ameliorates Liver Oxidative Damage and Promotes Regeneration

  • Adv Sci (Weinh). 2025 Mar 17:e2408724. doi: 10.1002/advs.202408724.
Nanfei Yang 1 2 3,  Qiang Tian 2,  Zhenli Lei 1,  Shuxin Wang 1,  Nan Cheng 4,  Zhen Wang 3,  Xianqin Jiang 1,  Xuqun Zheng 1,  Wenjing Xu 1,  Minyan Ye 1,  Longwei Zhao 5,  Meiyun Wen 5,  Jianlou Niu 1,  Weijian Sun 2,  Pingping Shen 2 3,  Zhifeng Huang 1,  Xiaokun Li 1
Affiliations

Affiliations

  • 1 Oujiang Laboratory (Zhejiang Lab for Regenerative Medicine, Vision, and Brain Health), State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
  • 2 Department of Colorectal Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325027, China.
  • 3 State Key Laboratory of Pharmaceutical Biotechnology and Clinical Stem Cell Center, The Affiliated Drum Tower Hospital of Nanjing University Medical School, School of Life Sciences, Nanjing University, Nanjing, 210023, China.
  • 4 School of Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, 210023, China.
  • 5 Department of Pharmacology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
PMID: 40091484 DOI: 10.1002/advs.202408724
Abstract

Liver regeneration is critical for maintaining whole-body homeostasis, especially under exposure to deadly chemical toxins. Understanding the molecular mechanisms underlying liver repair is critical for the development of intervention strategies to treat liver diseases. In this study, ubiquitin-specific Proteases 42 (USP42) is identified as a novel deubiquitinases (DUB) of peroxisome proliferators-activated receptor γ (PPARγ) in hepatocytes. This DUB interacted, deubiquitinated, and stabilized PPARγ, and increased PPARγ targeted proliferative and antioxidative gene expressions, which protects the liver from carbon tetrachloride (CCL4) induced oxidative injury and promotes liver regeneration. In addition, Fibroblast Growth Factor 2 (FGF2) initiated USP42 expression and enhanced the interaction between USP42 and PPARγ during the liver regeneration process. Moreover, the PPARγ full agonist, rosiglitazone (RSG), possesses the ability to further reinforce the USP42-PPARγ interplay, which enlightens to construct of an extracellular vesicle-based targeting strategy to activate the liver USP42-PPARγ axis and promote liver regeneration. In summary, the work uncovers the importance of USP42-PPARγ axis-mediated liver tissue homeostasis and provides a promising regimen to target this protein-protein interplay for liver regeneration.

Keywords

FGF2; PPARγ; USP42; liver regeneration; nano‐therapy; redox balance; ubiquitination.

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