Evidence map›Paper›PMID 42315669›Full record

ArticleApoptosis : an international journal on programmed cell death2026

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

Huaduan Zi, Hengcheng Tang, Xiaoxi Yang, Xiaojin Li, Yanmeng Li, Anjian Xu, Qin Ouyang, Sisi Chen, Pingping He, Yanling Li and 7 more

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Article in Apoptosis : an international journal on programmed cell death, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

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4 · The record

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5 · Who and what money

Authors and funding

17 authors.

Huaduan Zi *Laboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Hengcheng Tang *Laboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Xiaoxi YangLaboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Xiaojin LiLaboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Yanmeng LiLaboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Anjian XuLaboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Qin OuyangLaboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Sisi ChenLaboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Pingping HeLaboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Yanling LiLaboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Qianyu ZhuLaboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Bei ZhangLaboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Wei ZhangLiver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Xiaojuan OuLiver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China.
Liying SunDepartment of Critical Liver Diseases, Liver Research Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China. sunxlx@outlook.com.
Donghu ZhouLaboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. donghuzhou@ccmu.edu.cn.
Jian HuangLaboratory of Molecular Biology, Beijing Institute of Clinical Medicine, Beijing Friendship Hospital, Capital Medical University, Beijing, 100050, China. huangj1966@hotmail.com.

Funding

National Natural Science Foundation of China No. 81800451the Digestive Medical Coordinated Development Center of Beijing Municipal Administration of Hospitals no. XXX0101, XXZ0501, XXT03
6 · The paper itself

Abstract

purposeWilson 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.

methodsIntegrated 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

resultsCopper 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.

conclusionsUSP9X 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.

Indexed as

Caspase 3Caspase 9CopperJanus Kinase 1PyroptosisUbiquitin ThiolesteraseAnimalsHumansLiverMiceMice, KnockoutReactive Oxygen SpeciesSignal TransductionSTAT1 Transcription FactorUbiquitinationCaspase 3Caspase 9CopperJAK1 protein, humanJak1 protein, mouseJanus Kinase 1Reactive Oxygen SpeciesSTAT1 Transcription FactorUbiquitin ThiolesteraseUSP9X protein, humanUsp9x protein, mouseCopper toxicityGSDME-dependent pyroptosisInflammatory injuryJAK1/STAT1 pathwayUSP9X

Identifiers

PMID42315669

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.