Neurotoxicity of PM2.5-Bound Multi-Pollutant Mixtures in Parkinson’s Disease: Exploring the INPP5D/SHIP1-PI3K-AKT Axis via an Integrative Multi-Omics Study
4 affiliations
- 1Department of Neurology, Fujian Medical University Union Hospital, Fuzhou 350001, China
- 2Department of Epidemiology and Health Statistics, School of Public Health, Fujian Medical University, Fuzhou 350122, China
- 3Department of Bioinformatics, Fujian Key Laboratory of Medical Bioinformatics, School of Medical Technology and Engineering, Fujian Medical University, Fuzhou 350122, China
- 4Fujian Provincial Key Laboratory of Brain Aging and Neurodegenerative Diseases, School of Basic Medical Sciences, Fujian Medical University, Fuzhou 350122, China
Abstract
Accumulating epidemiological evidence links ambient PM2.5 exposure to elevated Parkinson’s disease (PD) risk, yet the neurotoxicity triggered by PM2.5 multi-pollutant mixtures under real co-exposure scenarios remains insufficiently elucidated. This study integrated two-sample Mendelian randomization (MR), mixture-oriented network toxicology, multi-omics bioinformatics, machine learning and in vitro cell validation to systematically uncover the causal molecular network of PD pathogenesis induced by mixed PM2.5 pollutants. Two-sample MR based on public GWAS datasets suggested a potential positive genetic association between PM2.5 exposure and increased PD susceptibility. We intersected PM2.5 component targets, PD risk genes and differential transcripts to obtain 195 shared genes, among which INPP5D (encoding SHIP1) was identified as the hub gene via LASSO and random forest algorithms. Molecular docking simulations further predicted that metal–organic pollutant complexes may exhibit stronger in-silico binding affinity toward SHIP1 than organic pollutants alone. Pathway enrichment screened the PI3K-AKT cascade as the core regulatory pathway. In SH-SY5Y cells, NIST SRM 1648a (urban particulate matter) treatment upregulated SHIP1 expression and phosphorylation, suppressed PI3K-AKT activity, and boosted neuroinflammation and apoptosis, whereas INPP5D knockdown rescued these pathological changes. Overall, our multi-omics and in vitro findings raise a plausible mechanistic hypothesis that NIST SRM 1648a-mimicked PM2.5-related pollutant mixtures may exacerbate PD-like neuronal injury through the SHIP1/PI3K-AKT signaling axis. This multi-dimensional evidence provides an analytical paradigm for mixed pollutant-induced neurodegeneration and highlights INPP5D as a promising intervention target for PM2.5-associated PD.
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BibTeX
@article{chen2026neurotoxicity,
title = {{Neurotoxicity of PM2.5-Bound Multi-Pollutant Mixtures in Parkinson’s Disease: Exploring the INPP5D/SHIP1-PI3K-AKT Axis via an Integrative Multi-Omics Study}},
author = {Lufei Chen and Chaoxian Dai and Zhenfang Wu and Yuhan Lin and Xiaoling Lin and Shenglang Chen and Mingzhi Fu and Yingqing Wang and Qinyong Ye},
journal = {Journal of xenobiotics},
year = {2026},
month = sep,
doi = {10.3390/jox16060184},
url = {https://europepmc.org/article/PMC/PMC13705901},
note = {CC BY},
}
RIS
TY - JOUR
TI - Neurotoxicity of PM2.5-Bound Multi-Pollutant Mixtures in Parkinson’s Disease: Exploring the INPP5D/SHIP1-PI3K-AKT Axis via an Integrative Multi-Omics Study
AU - Lufei Chen
AU - Chaoxian Dai
AU - Zhenfang Wu
AU - Yuhan Lin
AU - Xiaoling Lin
AU - Shenglang Chen
AU - Mingzhi Fu
AU - Yingqing Wang
AU - Qinyong Ye
PY - 2026
DA - 2026/09/01
JO - Journal of xenobiotics
DO - 10.3390/jox16060184
UR - https://europepmc.org/article/PMC/PMC13705901
AB - Accumulating epidemiological evidence links ambient PM2.5 exposure to elevated Parkinson’s disease (PD) risk, yet the neurotoxicity triggered by PM2.5 multi-pollutant mixtures under real co-exposure scenarios remains insufficiently elucidated. This study integrated two-sample Mendelian randomization (MR), mixture-oriented network toxicology, multi-omics bioinformatics, machine learning and in vitro cell validation to systematically uncover the causal molecular network of PD pathogenesis induced by mixed PM2.5 pollutants. Two-sample MR based on public GWAS datasets suggested a potential positive genetic association between PM2.5 exposure and increased PD susceptibility. We intersected PM2.5 component targets, PD risk genes and differential transcripts to obtain 195 shared genes, among which INPP5D (encoding SHIP1) was identified as the hub gene via LASSO and random forest algorithms. Molecular docking simulations further predicted that metal–organic pollutant complexes may exhibit stronger in-silico binding affinity toward SHIP1 than organic pollutants alone. Pathway enrichment screened the PI3K-AKT cascade as the core regulatory pathway. In SH-SY5Y cells, NIST SRM 1648a (urban particulate matter) treatment upregulated SHIP1 expression and phosphorylation, suppressed PI3K-AKT activity, and boosted neuroinflammation and apoptosis, whereas INPP5D knockdown rescued these pathological changes. Overall, our multi-omics and in vitro findings raise a plausible mechanistic hypothesis that NIST SRM 1648a-mimicked PM2.5-related pollutant mixtures may exacerbate PD-like neuronal injury through the SHIP1/PI3K-AKT signaling axis. This multi-dimensional evidence provides an analytical paradigm for mixed pollutant-induced neurodegeneration and highlights INPP5D as a promising intervention target for PM2.5-associated PD.
SN - 2039-4705
SN - 2039-4713
ER -