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Volume 14
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10.3390/toxics14020128
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Article

Combining Network Pharmacology and Experimental Verification to Investigate the Protective Effect of Melatonin on Fluoride-Induced Brain Injury

by
Runjiang Ma
1,2,3,
Chun Wang
1,2,3,
Wenqi Qin
1,2,3,
Yajie Li
1,2,3,
Meng Zhang
1,2,3,
Yongkang Liang
1,2,3,
Lu Wang
1,2,3,
Suya Wang
1,2,3,
Gaoxuan Xie
1,2,3 and
Qiang Niu
1,2,3,*
1
School of Public Health, Shihezi University, Shihezi 832000, China
2
Key Laboratory for Prevention and Control of Emerging Infectious Diseases and Public Health Security, Shihezi 832000, China
3
Key Laboratory of Xinjiang Endemic and Ethnic Diseases (Ministry of Education), School of Medicine, Shihezi University, Shihezi 832000, China
*
Author to whom correspondence should be addressed.
Toxics 2026, 14(2), 128; https://doi.org/10.3390/toxics14020128
Submission received: 30 December 2025 / Revised: 24 January 2026 / Accepted: 27 January 2026 / Published: 29 January 2026
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Abstract

Excessive fluoride exposure induces developmental neurotoxicity, but effective preventive strategies are currently scarce. Melatonin (Mel), a lipophilic hormone secreted by the pineal gland, exerts antioxidant, anti-inflammatory, and neuroprotective properties. This study aimed to explore Mel’s protective effect and mechanism against fluoride-induced developmental brain injury. We employed a network pharmacology approach to screen the common targets of Mel and fluoride-induced brain injury and performed enrichment analysis. A total of 189 common targets were identified, and these targets were mainly enriched in the HIF-1 signaling pathway and oxidative stress-related pathways. In vivo, Sprague Dawley rats were subjected to perinatal sodium fluoride (NaF) exposure with/without Mel; in vitro, HT22 cells were subjected to NaF and/or Mel. The results showed that Mel improved cognitive impairments and alleviated structural damage to hippocampal neurons and mitochondria. Furthermore, Mel upregulated SIRT3 and downregulated HIF-1α, thereby restoring mitochondrial oxidative phosphorylation and ATP content. This study demonstrates that Mel alleviates fluoride-induced developmental neurotoxicity by improving mitochondrial function through regulating the SIRT3/HIF-1α signaling pathway. This not only offers a novel perspective for elucidating the underlying molecular mechanisms of fluoride-induced developmental neurotoxicity but also provides a theoretical foundation for Mel as a potential protective candidate against fluoride exposure.
Keywords: melatonin; sodium fluoride; neurotoxicity; SIRT3/HIF-1α; energy metabolism; network pharmacology melatonin; sodium fluoride; neurotoxicity; SIRT3/HIF-1α; energy metabolism; network pharmacology

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MDPI and ACS Style

Ma, R.; Wang, C.; Qin, W.; Li, Y.; Zhang, M.; Liang, Y.; Wang, L.; Wang, S.; Xie, G.; Niu, Q. Combining Network Pharmacology and Experimental Verification to Investigate the Protective Effect of Melatonin on Fluoride-Induced Brain Injury. Toxics 2026, 14, 128. https://doi.org/10.3390/toxics14020128

AMA Style

Ma R, Wang C, Qin W, Li Y, Zhang M, Liang Y, Wang L, Wang S, Xie G, Niu Q. Combining Network Pharmacology and Experimental Verification to Investigate the Protective Effect of Melatonin on Fluoride-Induced Brain Injury. Toxics. 2026; 14(2):128. https://doi.org/10.3390/toxics14020128

Chicago/Turabian Style

Ma, Runjiang, Chun Wang, Wenqi Qin, Yajie Li, Meng Zhang, Yongkang Liang, Lu Wang, Suya Wang, Gaoxuan Xie, and Qiang Niu. 2026. "Combining Network Pharmacology and Experimental Verification to Investigate the Protective Effect of Melatonin on Fluoride-Induced Brain Injury" Toxics 14, no. 2: 128. https://doi.org/10.3390/toxics14020128

APA Style

Ma, R., Wang, C., Qin, W., Li, Y., Zhang, M., Liang, Y., Wang, L., Wang, S., Xie, G., & Niu, Q. (2026). Combining Network Pharmacology and Experimental Verification to Investigate the Protective Effect of Melatonin on Fluoride-Induced Brain Injury. Toxics, 14(2), 128. https://doi.org/10.3390/toxics14020128

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