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

  • Cell Death Differ. 2026 May 6. doi: 10.1038/s41418-026-01749-y.
Feng Shuang  #  1  2  3 ,  Nan Li  #  4  5 ,  Tianwei Guo  #  6 ,  Danfeng Zhang  #  7 ,  Hang Zhu  1  2 ,  Xin Jin  8 ,  XiaoLin Qu  9 ,  Ruting Wei  10 ,  Hui Luo  1  2 ,  Chao Lin  11  12
Affiliations
  • 1. Department of Neurosurgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China.
  • 2. Department of Neurosurgery, Jiangsu Province Hospital, Nanjing, China.
  • 3. Department of Neurosurgery, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing, University of Chinese Medicine, Nanjing, China.
  • 4. Department of Nephrology, Nanjing Drum Tower Hospital, Drum Tower Clinical College of Nanjing Medical University, Nanjing, China.
  • 5. Department of Nephrology, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 6. Department of Pathology, Changshu Hospital Affiliated to Nanjing University of Chinese Medicine, Changshu City, China.
  • 7. Department of Neurosurgery, Changzheng Hospital, Naval Medical University, Shanghai, China.
  • 8. Department of Health Management Center, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, China.
  • 9. Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
  • 10. Department of Neurosurgery, The Affiliated Hospital of Guizhou Medical University, Guiyang, China.
  • 11. Department of Neurosurgery, The First Affiliated Hospital with Nanjing Medical University, Nanjing, China. [email protected].
  • 12. Department of Neurosurgery, Jiangsu Province Hospital, Nanjing, China. [email protected].
  • # Contributed equally.
PMID: 42091674 DOI: 10.1038/s41418-026-01749-y
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.

Products