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USP4 modulates ZBP1 ubiquitination to regulate microglial PANoptosis and functional outcomes following traumatic brain injury

Cell Death & Differentiation (2026) Cite this article

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Abstract

Secondary damage in traumatic brain injury (TBI) is characterized by the abnormal release of damage-associated molecular patterns and excessive production of pro-inflammatory cytokines. Neuroinflammation is a hallmark of TBI. However, the mechanisms through which immune cells contribute to cognitive deficits and secondary inflammatory pathology remain poorly understood. In this study, we found that ZBP1-mediated microglial PANoptosis, which is a distinct form of innate immune-driven inflammatory cell death, is triggered following TBI. We further determined that microglial PANoptosis is induced by the synergistic action of heme and TNF-α. Mechanistically, we identified USP4 as a critical deubiquitinase for ZBP1 in microglia. USP4 was found to interact with, deubiquitinate, and stabilize ZBP1. Notably, AKT-mediated phosphorylation was found to be essential for maintaining USP4 protein stability. Pharmacological inhibition of USP4 using Vialinin A led to ZBP1 degradation, reduced microglial PANoptosis, and the amelioration of TBI-related functional deficits. Moreover, USP4 expression levels were found to be negatively correlated with prognosis patients with severe TBI. Collectively, our findings highlight a crucial role for USP4 in facilitating ZBP1-mediated inflammasome activation, microglial death, and cognitive impairment post-TBI, underscoring its potential as a therapeutic target.

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Fig. 1: TBI induces microglial PANoptosis.
The alternative text for this image may have been generated using AI.
Fig. 2: Heme and TNF-α co-treatment induce microglial death.
The alternative text for this image may have been generated using AI.
Fig. 3: USP4 stabilizes ZBP1 to promote PANoptosis following TBI.
The alternative text for this image may have been generated using AI.
Fig. 4: USP4 mediates de-polyubiquitination of ZBP1.
The alternative text for this image may have been generated using AI.
Fig. 5: AKT-mediated phosphorylation stabilizes USP4 following TBI.
The alternative text for this image may have been generated using AI.
Fig. 6: Engineered nanoparticle-mediated delivery of USP4 inhibitor attenuates neuroinflammation and enhances neurological recovery following TBI.
The alternative text for this image may have been generated using AI.
Fig. 7: Vialinin A treatment mitigates histological and neurocognitive impairments in mice following CCI.
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Fig. 8: USP4 expression significantly predicts outcomes in sTBI patients.
The alternative text for this image may have been generated using AI.
Fig. 9: Schematic Illustration of Microglial PANoptosis in TBI.
The alternative text for this image may have been generated using AI.

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Data availability

We declare that all the data and materials are available upon request.

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Acknowledgements

The authors would like to thank all the reviewers who participated in the review.

Funding

This work was supported by the Natural Science Foundation of China (NSFC) (81901258 to Chao Lin and 82271396 to Danfeng Zhang).

Author information

Author notes

  1. These authors contributed equally: Feng shuang, Nan Li, Tianwei Guo, Danfeng Zhang.

Authors and Affiliations

  1. Department of Neurosurgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China

    Feng shuang, Hang Zhu, Hui Luo & Chao Lin

  2. Department of Neurosurgery, Jiangsu Province Hospital, Nanjing, China

    Feng shuang, Hang Zhu, Hui Luo & Chao Lin

  3. Department of Neurosurgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing, University of Chinese Medicine, Nanjing, China

    Feng shuang

  4. Department of Nephrology, Nanjing Drum Tower Hospital, Drum Tower Clinical College of Nanjing Medical University, Nanjing, China

    Nan Li

  5. Department of Nephrology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

    Nan Li

  6. Department of Pathology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu City, China

    Tianwei Guo

  7. Department of Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China

    Danfeng Zhang

  8. Department of Health Management Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China

    Xin Jin

  9. Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China

    XiaoLin Qu

  10. Department of Neurosurgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China

    Ruting Wei

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Contributions

CL, SF, NL, TWG, DFZ, and HL designed the research and analyzed data. ZH, XJ, XLQ, and RTW performed experiments and analyzed data. CL and SF wrote the manuscript.

Corresponding author

Correspondence to Chao Lin.

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The authors declare no competing interests.

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All animal experiments were approved by Nanjing Medical University (2025-487). Human tissue collection and subsequent studies were approved by the Ethical Committee of the First Affiliated Hospital with Nanjing Medical University (2025-SRFA-801). The human aspect of our study complied with the Declaration of Helsinki and Principles of Good Clinical Practice. Informed consent was signed by each patient or her/his legal representative.

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shuang, F., Li, N., Guo, T. et al. USP4 modulates ZBP1 ubiquitination to regulate microglial PANoptosis and functional outcomes following traumatic brain injury. Cell Death Differ (2026). https://doi.org/10.1038/s41418-026-01749-y

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