Study on the mechanism of diethyltoluamide mediated vascular dementia based on network toxicology and molecular docking_West China Medical Journal

Authors：

ZHAO Zhenkun ^1,2 , PAN Zhongjing ^1,2 , YAO Peng ^1,2 , CAO Yu ^1,2 ,  GAN Lu ^1,2

1. Department of Emergency Medicine, Institute of Disaster Medicine and Institute of Emergency Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P. R. China;
2. Disaster Medicine Center, Sichuan University, Chengdu, Sichuan 610041, P. R. China;

Corresponding?author：

GAN Lu, Email: ganlu@wchscu.cn

Keywords：

Diethyltoluamide; vascular dementia; network toxicology; molecular docking

DOI：

10.7507/1002-0179.202510032

Video：

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Objective To investigate the potential association between diethyltoluamide and the risk of vascular dementia (VaD), and to predict its core targets and molecular mechanisms using network toxicology and molecular docking. Methods The toxicological characteristics and potential targets of diethyltoluamide were predicted using toxicological databases. VaD-related targets were retrieved from disease databases. The STRING database was used to construct a protein-protein interaction network to screen core genes. Pathway enrichment analyses were conducted on the intersecting genes. Finally, the key protein was selected and its binding affinity with diethyltoluamide was verified through molecular docking technology. Results Network toxicology analysis identified 71 common targets of diethyltoluamide and VaD. Core targets included TNF, TP53, ACTB, HSP90AA1, and KRAS. These targets were enriched in cellular response to oxidative stress, inflammatory response, and apoptotic signaling pathway, as well as key signaling pathways including PI3K-Akt, mitogen-activated protein kinase. Molecular docking confirmed that diethyltoluamide exhibited strong binding affinity with these core targets. Conclusions Diethyltoluamide may participate in the pathological process of VaD by directly acting on multiple core targets such as TNF, TP53, and KRAS, thereby interfering with various pathways including neuroinflammation, oxidative stress, and cerebrovascular regulation.

Citation： ZHAO Zhenkun, PAN Zhongjing, YAO Peng, CAO Yu, GAN Lu. Study on the mechanism of diethyltoluamide mediated vascular dementia based on network toxicology and molecular docking. West China Medical Journal, 2025, 40(11): 1794-1798. doi: 10.7507/1002-0179.202510032 Copy

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11.	Nihart AJ, Garcia MA, El Hayek E, et al. Bioaccumulation of microplastics in decedent human brains. Nat Med, 2025, 31(4): 1114-1119.
12.	Yan Y, Maisenbacher M, Huang C, et al. Detoxification and age-related neurodegenerative diseases: correlation and therapeutic potential. Pharmacol Res, 2025, 218: 107849.
13.	Leng Y, Zeng Y, Zhang Y, et al. Neurotoxic risks of long-term environmental exposure to pesticides: a review. Chem Biol Interact, 2025, 418: 111626.
14.	Yan S, Wang J, Xu J, et al. Exposure to N, N-diethyl-m-toluamide and cardiovascular diseases in adults. Front Public Health, 2022, 10: 922005.
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16.	Cheng M, Li M, Zhang Y, et al. Exploring the mechanism of PPCPs on human metabolic diseases based on network toxicology and molecular docking. Environ Int, 2025, 196: 109324.
17.	Del Giudice G, Serra A, Pavel A, et al. A network toxicology approach for mechanistic modelling of nanomaterial hazard and adverse outcomes. Adv Sci (Weinh), 2024, 11(32): e2400389.
18.	Li Y, Zhou T, Liu Z, et al. Air pollution and prostate cancer: unraveling the connection through network toxicology and machine learning. Ecotoxicol Environ Saf, 2025, 292: 117966.
19.	Li NR, Zeng YX, Gu YF, et al. Aspartame increases the risk of liver cancer through CASP1 protein: a comprehensive network analysis insight. Ecotoxicol Environ Saf, 2025, 294: 118089.
20.	Yang K, Zhou X, Wu K, et al. Multi-omics reveals the polyethylene terephthalate carcinogenicity: cancer progression and immune microenvironment. Ecotoxicol Environ Saf, 2025, 302: 118522.
21.	Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: customizable protein-protein networks and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res, 2021, 49(D1): D605-D612.
22.	Yang J, Zhong J, Du Y, et al. Bioinformatics and systems biology approaches to identify potential common pathogeneses for sarcopenia and osteoarthritis. Front Med (Lausanne), 2024, 11: 1380210.
23.	Pinzi L, Rastelli G. Molecular docking: shifting paradigms in drug discovery. Int J Mol Sci, 2019, 20(18): 4331.
24.	Abdel-Rahman A, Dechkovskaia AM, Goldstein LB, et al. Neurological deficits induced by malathion, DEET, and permethrin, alone or in combination in adult rats. J Toxicol Environ Health A, 2004, 67(4): 331-356.
25.	Abdel-Rahman A, Abou-Donia S, El-Masry E, et al. Stress and combined exposure to low doses of pyridostigmine bromide, DEET, and permethrin produce neurochemical and neuropathological alterations in cerebral cortex, hippocampus, and cerebellum. J Toxicol Environ Health A, 2004, 67(2): 163-192.
26.	Michalovicz LT, Locker AR, Kelly KA, et al. Corticosterone and pyridostigmine/DEET exposure attenuate peripheral cytokine expression: supporting a dominant role for neuroinflammation in a mouse model of Gulf War Illness. Neurotoxicology, 2019, 70: 26-32.
27.	Belarbi K, Jopson T, Tweedie D, et al. TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J Neuroinflammation, 2012, 9: 23.
28.	Li H, Zhang Z, Li H, et al. New insights into the roles of p53 in central nervous system diseases. Int J Neuropsychopharmacol, 2023, 26(7): 465-473.
29.	Ham SW, Jeon HY, Jin X, et al. TP53 gain-of-function mutation promotes inflammation in glioblastoma. Cell Death Differ, 2019, 26(3): 409-425.
30.	Wang F, Wang Q, Liu B, et al. The long noncoding RNA synage regulates synapse stability and neuronal function in the cerebellum. Cell Death Differ, 2021, 28(9): 2634-2650.
31.	Lei W, Yiming S, Qiang P, et al. Unleashing the neurotherapeutic potential: the crucial role of miR-206-3p in facilitating Hsp90aa1-mediated central nervous system injuries during heat stroke. Mol Neurobiol, 2025, 62(2): 1433-1450.
32.	Zhong J. RAS and downstream RAF-MEK and PI3K-AKT signaling in neuronal development, function and dysfunction. Biol Chem, 2016, 397(3): 215-222.
33.	Ryu HH, Kang M, Hwang KD, et al. Neuron type-specific expression of a mutant KRAS impairs hippocampal-dependent learning and memory. Sci Rep, 2020, 10(1): 17730.
34.	Wu T, Jia L, Lei S, et al. Host HSPD1 translocation from mitochondria to the cytoplasm induced by Streptococcus suis serovar 2 enolase mediates apoptosis and loss of blood-brain barrier integrity. Cells, 2022, 11(13): 2071.

1. Calafat AM, Baker SE, Wong LY, et al. Novel exposure biomarkers of N, N-diethyl-m-toluamide (DEET): data from the 2007-2010 National Health and Nutrition Examination Survey. Environ Int, 2016(92/93): 398-404.
2. Chen-Hussey V, Behrens R, Logan JG. Assessment of methods used to determine the safety of the topical insect repellent N, N-diethyl-m-toluamide (DEET). Parasit Vectors, 2014, 7: 173.
3. Weeks JA, Guiney PD, Nikiforov AI. Assessment of the environmental fate and ecotoxicity of N, N-diethyl-m-toluamide (DEET). Integr Environ Assess Manag, 2012, 8(1): 120-134.
4. Zhao X, Li J, Liu Y, et al. A prospective cohort study of exposure to household pesticide with cardiovascular diseases mortality in older adults. J Hazard Mater, 2024, 471: 134316.
5. Swale DR, Bloomquist JR. Is DEET a dangerous neurotoxicant?. Pest Manag Sci, 2019, 75(8): 2068-2070.
6. Corbel V, Stankiewicz M, Pennetier C, et al. Evidence for inhibition of cholinesterases in insect and mammalian nervous systems by the insect repellent deet. BMC Biol, 2009, 7: 47.
7. Swale DR, Sun B, Tong F, et al. Neurotoxicity and mode of action of N, N-diethyl-meta-toluamide (DEET). PLoS One, 2014, 9(8): e103713.
8. Iadecola C, Duering M, Hachinski V, et al. Vascular cognitive impairment and dementia: JACC scientific expert panel. J Am Coll Cardiol, 2019, 73(25): 3326-3344.
9. Tian M, Kawaguchi R, Shen Y, et al. Deconstructing the intercellular interactome in vascular dementia with focal ischemia for therapeutic applications. Cell, 2025, 188(19): 5157-5174.e20.
10. Wolters FJ, Ikram MA. Epidemiology of vascular dementia. Arterioscler Thromb Vasc Biol, 2019, 39(8): 1542-1549.
11. Nihart AJ, Garcia MA, El Hayek E, et al. Bioaccumulation of microplastics in decedent human brains. Nat Med, 2025, 31(4): 1114-1119.
12. Yan Y, Maisenbacher M, Huang C, et al. Detoxification and age-related neurodegenerative diseases: correlation and therapeutic potential. Pharmacol Res, 2025, 218: 107849.
13. Leng Y, Zeng Y, Zhang Y, et al. Neurotoxic risks of long-term environmental exposure to pesticides: a review. Chem Biol Interact, 2025, 418: 111626.
14. Yan S, Wang J, Xu J, et al. Exposure to N, N-diethyl-m-toluamide and cardiovascular diseases in adults. Front Public Health, 2022, 10: 922005.
15. Xu Z, Wang A, Hu J, et al. Elucidating the mechanisms of environmental pollutant BPA inducing neurotoxicity through metabolomics and network toxicology strategy. Environ Pollut, 2025, 381: 126591.
16. Cheng M, Li M, Zhang Y, et al. Exploring the mechanism of PPCPs on human metabolic diseases based on network toxicology and molecular docking. Environ Int, 2025, 196: 109324.
17. Del Giudice G, Serra A, Pavel A, et al. A network toxicology approach for mechanistic modelling of nanomaterial hazard and adverse outcomes. Adv Sci (Weinh), 2024, 11(32): e2400389.
18. Li Y, Zhou T, Liu Z, et al. Air pollution and prostate cancer: unraveling the connection through network toxicology and machine learning. Ecotoxicol Environ Saf, 2025, 292: 117966.
19. Li NR, Zeng YX, Gu YF, et al. Aspartame increases the risk of liver cancer through CASP1 protein: a comprehensive network analysis insight. Ecotoxicol Environ Saf, 2025, 294: 118089.
20. Yang K, Zhou X, Wu K, et al. Multi-omics reveals the polyethylene terephthalate carcinogenicity: cancer progression and immune microenvironment. Ecotoxicol Environ Saf, 2025, 302: 118522.
21. Szklarczyk D, Gable AL, Nastou KC, et al. The STRING database in 2021: customizable protein-protein networks and functional characterization of user-uploaded gene/measurement sets. Nucleic Acids Res, 2021, 49(D1): D605-D612.
22. Yang J, Zhong J, Du Y, et al. Bioinformatics and systems biology approaches to identify potential common pathogeneses for sarcopenia and osteoarthritis. Front Med (Lausanne), 2024, 11: 1380210.
23. Pinzi L, Rastelli G. Molecular docking: shifting paradigms in drug discovery. Int J Mol Sci, 2019, 20(18): 4331.
24. Abdel-Rahman A, Dechkovskaia AM, Goldstein LB, et al. Neurological deficits induced by malathion, DEET, and permethrin, alone or in combination in adult rats. J Toxicol Environ Health A, 2004, 67(4): 331-356.
25. Abdel-Rahman A, Abou-Donia S, El-Masry E, et al. Stress and combined exposure to low doses of pyridostigmine bromide, DEET, and permethrin produce neurochemical and neuropathological alterations in cerebral cortex, hippocampus, and cerebellum. J Toxicol Environ Health A, 2004, 67(2): 163-192.
26. Michalovicz LT, Locker AR, Kelly KA, et al. Corticosterone and pyridostigmine/DEET exposure attenuate peripheral cytokine expression: supporting a dominant role for neuroinflammation in a mouse model of Gulf War Illness. Neurotoxicology, 2019, 70: 26-32.
27. Belarbi K, Jopson T, Tweedie D, et al. TNF-α protein synthesis inhibitor restores neuronal function and reverses cognitive deficits induced by chronic neuroinflammation. J Neuroinflammation, 2012, 9: 23.
28. Li H, Zhang Z, Li H, et al. New insights into the roles of p53 in central nervous system diseases. Int J Neuropsychopharmacol, 2023, 26(7): 465-473.
29. Ham SW, Jeon HY, Jin X, et al. TP53 gain-of-function mutation promotes inflammation in glioblastoma. Cell Death Differ, 2019, 26(3): 409-425.
30. Wang F, Wang Q, Liu B, et al. The long noncoding RNA synage regulates synapse stability and neuronal function in the cerebellum. Cell Death Differ, 2021, 28(9): 2634-2650.
31. Lei W, Yiming S, Qiang P, et al. Unleashing the neurotherapeutic potential: the crucial role of miR-206-3p in facilitating Hsp90aa1-mediated central nervous system injuries during heat stroke. Mol Neurobiol, 2025, 62(2): 1433-1450.
32. Zhong J. RAS and downstream RAF-MEK and PI3K-AKT signaling in neuronal development, function and dysfunction. Biol Chem, 2016, 397(3): 215-222.
33. Ryu HH, Kang M, Hwang KD, et al. Neuron type-specific expression of a mutant KRAS impairs hippocampal-dependent learning and memory. Sci Rep, 2020, 10(1): 17730.
34. Wu T, Jia L, Lei S, et al. Host HSPD1 translocation from mitochondria to the cytoplasm induced by Streptococcus suis serovar 2 enolase mediates apoptosis and loss of blood-brain barrier integrity. Cells, 2022, 11(13): 2071.

West China Medical Journal

Study on the mechanism of diethyltoluamide mediated vascular dementia based on network toxicology and molecular docking

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