USP9X regulates copper-induced CASP9/CASP3/GSDME-dependent pyroptosis by deubiquitinating JAK1

  • Apoptosis. 2026 Jun 18;31(7):177. doi: 10.1007/s10495-026-02379-y.
Huaduan Zi  #  1  2  3  4 ,  Hengcheng Tang  #  1  2  3 ,  Xiaoxi Yang  1  5 ,  Xiaojin Li  1  2  3 ,  Yanmeng Li  1  2  3 ,  Anjian Xu  1  2  3 ,  Qin Ouyang  1  2  3 ,  Sisi Chen  1  2  3 ,  Pingping He  1  2  3 ,  Yanling Li  1  2  3 ,  Qianyu Zhu  1  2  3 ,  Bei Zhang  1  2  3 ,  Wei Zhang  6 ,  Xiaojuan Ou  6 ,  Liying Sun  7 ,  Donghu Zhou  8  9  10  11 ,  Jian Huang  12  13  14  15
Affiliations
  • 1. Laboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
  • 2. State Key Laboratory of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 3. National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 4. Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
  • 5. Clinical Research Center, Beijing Children's Hospital, Capital Medical University, Beijing, China.
  • 6. Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
  • 7. Department of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China. [email protected].
  • 8. Laboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. [email protected].
  • 9. State Key Laboratory of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China. [email protected].
  • 10. National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China. [email protected].
  • 11. Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. [email protected].
  • 12. Laboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. [email protected].
  • 13. State Key Laboratory of Digestive Health, Beijing Friendship Hospital, Capital Medical University, Beijing, China. [email protected].
  • 14. National Clinical Research Center for Digestive Diseases, Beijing Friendship Hospital, Capital Medical University, Beijing, China. [email protected].
  • 15. Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. [email protected].
  • # Contributed equally.
PMID: 42315669 DOI: 10.1007/s10495-026-02379-y
Abstract

Purpose: Wilson disease (WD) is characterized by hepatic injury caused by copper accumulation; however, the underlying molecular mechanisms remain incompletely understood. This study aims to investigate whether copper overload induces Pyroptosis in WD and to elucidate the role of USP9X-mediated JAK1 deubiquitination in this process.

Methods: Integrated transcriptomic, proteomic, and ubiquitinomic analyses were performed on liver tissues from WD patients and ATP7B-knockout cellular models. The involvement of the JAK1/STAT1 signaling pathway, the CASP9/CASP3/GSDME axis, and USP9X-mediated deubiquitination was further investigated using pharmacological inhibition as well as gene knockout and knockdown approaches, and the findings were subsequently validated in Atp7b-/- mouse models.

Results: Copper overload markedly activated the JAK1/STAT1 signaling pathway, enhanced Reactive Oxygen Species (ROS) production, and triggered activation of CASP9 and CASP3, resulting in GSDME cleavage and a switch from hepatocyte Apoptosis to Pyroptosis. Mechanistically, copper upregulated USP9X expression, which mediated the deubiquitination of JAK1 at lysine 249, thereby stabilizing JAK1 and enhancing downstream signaling cascade. Pharmacological or genetic inhibition of JAK1/STAT1 pathway or GSDME significantly attenuated Pyroptosis and alleviated liver injury in WD mouse models, even in the presence of persistent copper accumulation.

Conclusions: USP9X deubiquitinates JAK1, thereby promoting copper-induced CASP9/CASP3/GSDME-dependent Pyroptosis and liver injury in WD. Targeting the USP9X/JAK1 axis may represent a promising therapeutic strategy for WD.

Keywords
Copper toxicity; GSDME-dependent pyroptosis; Inflammatory injury; JAK1/STAT1 pathway; USP9X.
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