2. Academic Validation
  3. Zinc-α₂-glycoprotein overexpression attenuates gasdermin D-mediated pyroptosis in dopaminergic neurons by suppressing reactive oxygen species/mitogen-activated protein kinase signaling

Zinc-α₂-glycoprotein overexpression attenuates gasdermin D-mediated pyroptosis in dopaminergic neurons by suppressing reactive oxygen species/mitogen-activated protein kinase signaling

  • Int J Biol Macromol. 2026 Feb;343(Pt 2):150185. doi: 10.1016/j.ijbiomac.2026.150185.
Lijuan Mo 1,  Jianhe Yue 2,  Changhong Tan 1,  Ying Liu 1,  Lin Han 3,  Wuxue Peng 1,  WeiNa Li 1,  Qi Yang 1,  Xi Liu 4,  Lifen Chen 5
Affiliations

Affiliations

  • 1 Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 2 Department of Neurosurgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China.
  • 3 Department of Neurology, West China School of Public Health and West China Fourth Hospital, Sichuan University, Chengdu, China.
  • 4 Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
  • 5 Department of Neurology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China. Electronic address: [email protected].
PMID: 41520969 DOI: 10.1016/j.ijbiomac.2026.150185
Abstract

Zinc-α₂-glycoprotein (ZAG) is a multifunctional regulator of metabolism and inflammation, yet its role in pyroptosis-an inflammatory form of cell death-remains unexplored. This study investigates ZAG's function in dopaminergic neuron Pyroptosis, a key driver of neuronal death in Parkinson's disease (PD), using MPP+-treated SH-SY5Y cells and MPTP-treated C57BL/6J mice as PD models. We demonstrate significant downregulation of ZAG expression in both MPP+-treated cells and substantia nigra dopaminergic neurons of MPTP-treated mice. Neuron-targeted ZAG overexpression (achieved via lentivirus in vitro and Adeno-Associated Virus in vivo) suppressed NLRP3 inflammasome activation, Caspase-1 cleavage, and Gasdermin D (GSDMD)-Mediated Inflammatory Pyroptosis, reducing levels of key pro-inflammatory signaling molecules (HMGB1, IL-1β, IL-18). Conversely, ZAG knockdown in vitro or dopaminergic neuron-specific AZGP1 knockout in vivo exacerbated these pyroptotic and inflammatory effects. Critically, restoring ZAG expression attenuated dopaminergic neuron degeneration and rescued motor deficits in PD models. Mechanistically, ZAG deficiency promoted Pyroptosis via Reactive Oxygen Species (ROS) overproduction and elevated malondialdehyde. Transcriptomic analysis identified MAPK signaling as the core pathway regulated by ZAG, and co-immunoprecipitation coupled with molecular docking revealed a novel direct ZAG-JNK interaction that inhibits JNK phosphorylation. This interaction suppressed neuronal Pyroptosis, while pharmacologic JNK activation abolished ZAG's neuroprotection. Our findings establish ZAG as an endogenous neuroprotectant that mitigates dopaminergic neuron loss through dual mechanisms: attenuating oxidative stress and directly inhibiting the NLRP3 inflammasome-pyroptosis axis via JNK binding. This positions ZAG restoration as a promising multi-target therapeutic strategy for PD.

Keywords

Mitogen-activated protein kinase; Pyroptosis; Zinc-α₂-glycoprotein.

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