Anacardic acid mitigates traumatic brain injury-induced inflammatory damage: involvement of TLR4/MyD88/NF-κB pathway regulation and inhibition of P300 HAT activity on NF-κB acetylation

  • Int Immunopharmacol. 2026 Jun 15:179:116613. doi: 10.1016/j.intimp.2026.116613.
Chenguang Yang  1 ,  Junnan Ru  2 ,  Xingxing Zhang  3 ,  Xiaobin Kong  1 ,  Chaoran Zhu  1 ,  Zhuqi Gao  1 ,  Fatao Chen  1 ,  Kaiwei Zheng  1 ,  Kunlin Jin  4 ,  Qichuan Zhuge  5 ,  Su Yang  6 ,  Lijie Huang  7
Affiliations
  • 1. Zhejiang - US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
  • 2. Zhejiang - US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Zhejiang Cancer Hospital, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou 310022, China.
  • 3. Department of Operation room, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China.
  • 4. Department of Pharmacology and Neuroscience, University of North Texas Health Science Center, FortWorth, TX, United States.
  • 5. Zhejiang - US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: [email protected].
  • 6. Zhejiang - US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: [email protected].
  • 7. Zhejiang - US Joint Laboratory for Aging and Neurological Disease Research, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China; Department of Neurosurgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325000, China. Electronic address: [email protected].
PMID: 41950807 DOI: 10.1016/j.intimp.2026.116613
Abstract

Introduction: Traumatic brain injury (TBI) triggers neuroinflammation and NLRP3 inflammasome-dependent Pyroptosis, causing substantial neuronal damage. Anacardic acid (AA), a natural Histone Acetyltransferase (HAT) inhibitor, has anti-inflammatory properties related to TBI. This study explored AA's effects on Pyroptosis and its neuroprotective potential after TBI.

Methods: A controlled cortical impact (CCI) mouse model was employed. Neurological recovery was evaluated by mNSS and rotarod tests, lesion volume by H&E staining, and neuronal survival by NeuN/TUNEL immunofluorescence. Inflammatory cytokines were measured via ELISA, and inflammatory-related proteins by western blotting. Pyroptosis was assessed through LDH release, GSDMD cleavage, and microglial IBA-1/cleaved Caspase-1 (p20) immunostaining. The role of P300 in NF-κB acetylation was determined using CTB (an activator of HAT) and P300 knockdown via siRNA.

Results: AA treatment reduced brain lesion volume, improved neurological function, and promoted cortical neuronal survival. It significantly decreased pro-inflammatory cytokine levels (IL-1β, IL-6, IL-18, TNF-α), inhibited NLRP3 inflammasome assembly, and blocked microglial Pyroptosis. AA also suppressed the TLR4/MyD88/NF-κB pathway and upstream NF-κB activation. Remarkably, p300 knockdown exacerbated NF-κB acetylation and NLRP3 inflammasome assembly, while CTB administration reversed these effects.

Conclusions: AA confers neuroprotection in TBI by alleviating neuroinflammation and NLRP3-dependent Pyroptosis. This is achieved by inhibiting the TLR4/MyD88/NF-κB pathway and suppressing p300-mediated NF-κB acetylation, suggesting AA's therapeutic potential for TBI.

Keywords
Anacardic acid; Gasdermin D; Pyroptosis; TLR4/MyD88/NF-κB pathway; Traumatic brain injury.
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