Systems Toxicology Indicates AKT1/PTGS2‐Centered Neuroinflammatory‐Mitochondrial Crosstalk in Lidocaine Associated Neurotoxicity
- 1Department of Pediatrics, the First Dongguan Affiliated Hospital Guangdong Medical University Dongguan Guangdong China
- 2Dongguan Innovation Institute The First Dongguan Affiliated Hospital, Guangdong Medical University Dongguan Guangdong China
- 3Guangdong Provincial Key Laboratory of Medical Immunology and Molecular Diagnostics The First Dongguan Affiliated Hospital, Guangdong Medical University Dongguan China
Abstract
Background: Lidocaine‐containing teething gels are commonly used for pediatric oral analgesia, yet excessive exposure may induce severe neurotoxic effects, including seizure‐related events. The molecular mechanisms underlying lidocaine‐associated neurotoxicity remain poorly defined.
Methods: We employed an integrative systems toxicology approach combining network toxicology, transcriptomic analysis (GSE143272), weighted gene co‐expression network analysis, molecular docking, molecular dynamics simulation, and experimental validation using Kamistad Gel extract at defined lidocaine‐equivalent concentration to characterize the molecular basis of lidocaine‐induced neurotoxicity.
Results: Sixteen shared targets were identified through the integration of lidocaine‐related targets, epilepsy‐associated genes, and transcriptomic signatures. AKT1 and PTGS2 emerged as key hub genes. Functional analyses consistently suggested neuroinflammatory signaling, mitochondrial dysfunction, and synaptic dysregulation as major pathogenic mechanisms. Molecular docking and 10‐ns molecular dynamics simulations indicated stable interactions between lidocaine and AKT1/PTGS2. ROC analysis indicated moderate predictive performance of these genes in epilepsy datasets. In SH‐SY5Y cells, Kamistad Gel extract significantly increased AKT1 and PTGS2 expression, supporting activation of inflammation‐related neurotoxic pathways.
Conclusions: Lidocaine‐associated neurotoxicity may involve an AKT1/PTGS2‐centered neuroinflammatory–mitochondrial crosstalk network accompanied by synaptic dysfunction. This study provides a systems‐level mechanistic insight into lidocaine neurotoxicity and identifies potential targets for improving the safety of pediatric lidocaine‐containing formulations.
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BibTeX
@article{jiang2026systems,
title = {{Systems Toxicology Indicates AKT1/PTGS2‐Centered Neuroinflammatory‐Mitochondrial Crosstalk in Lidocaine Associated Neurotoxicity}},
author = {Min Jiang and Liping Chen and Jingyi Deng and Hangyu Li and Yuqia Xie and Xueqin Huang and Weidong Liu and Suidong Ouyang},
journal = {CNS Neuroscience \& Therapeutics},
year = {2026},
month = oct,
doi = {10.1002/cns.71218},
url = {https://doi.org/10.1002/cns.71218},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Systems Toxicology Indicates AKT1/PTGS2‐Centered Neuroinflammatory‐Mitochondrial Crosstalk in Lidocaine Associated Neurotoxicity
AU - Min Jiang
AU - Liping Chen
AU - Jingyi Deng
AU - Hangyu Li
AU - Yuqia Xie
AU - Xueqin Huang
AU - Weidong Liu
AU - Suidong Ouyang
PY - 2026
DA - 2026/10/01
JO - CNS Neuroscience & Therapeutics
DO - 10.1002/cns.71218
UR - https://doi.org/10.1002/cns.71218
AB - Background: Lidocaine‐containing teething gels are commonly used for pediatric oral analgesia, yet excessive exposure may induce severe neurotoxic effects, including seizure‐related events. The molecular mechanisms underlying lidocaine‐associated neurotoxicity remain poorly defined. Methods: We employed an integrative systems toxicology approach combining network toxicology, transcriptomic analysis (GSE143272), weighted gene co‐expression network analysis, molecular docking, molecular dynamics simulation, and experimental validation using Kamistad Gel extract at defined lidocaine‐equivalent concentration to characterize the molecular basis of lidocaine‐induced neurotoxicity. Results: Sixteen shared targets were identified through the integration of lidocaine‐related targets, epilepsy‐associated genes, and transcriptomic signatures. AKT1 and PTGS2 emerged as key hub genes. Functional analyses consistently suggested neuroinflammatory signaling, mitochondrial dysfunction, and synaptic dysregulation as major pathogenic mechanisms. Molecular docking and 10‐ns molecular dynamics simulations indicated stable interactions between lidocaine and AKT1/PTGS2. ROC analysis indicated moderate predictive performance of these genes in epilepsy datasets. In SH‐SY5Y cells, Kamistad Gel extract significantly increased AKT1 and PTGS2 expression, supporting activation of inflammation‐related neurotoxic pathways. Conclusions: Lidocaine‐associated neurotoxicity may involve an AKT1/PTGS2‐centered neuroinflammatory–mitochondrial crosstalk network accompanied by synaptic dysfunction. This study provides a systems‐level mechanistic insight into lidocaine neurotoxicity and identifies potential targets for improving the safety of pediatric lidocaine‐containing formulations.
SN - 1755-5930
SN - 1755-5949
ER -