Inositol-Dependent Alleviation of Lithium-Induced Embryonic Neurotoxicity in Mice Through the GSK3β/β-Catenin/CyclinD1 Pathway
- 1Capital Center for Children’s Health, Capital Medical University, Capital Institute of Pediatrics, No. 2 Yabao Road, Chaoyang District, Beijing 100020, China
Abstract
Lithium carbonate (Li2CO3) is a first-line pharmacotherapy for bipolar disorder (BPD) in female patients of childbearing age, although it is associated with embryonic teratogenicity. Lithium exposure in batteries and pharmaceuticals has been a toxicity factor for women’s reproductive health in energy, environment, and fitness fields. Neural tube defects (NTDs) are the severest reproductive outcome of maternal Li2CO3 exposure. Currently, there is a lack of effective prevention for Li2CO3 neurotoxicity. Our previous study revealed that lithium-induced murine NTDs correlated with enhanced proliferation and impaired inositol biosynthesis. In this study, 400 mg/kg inositol was used to treat the lithium-induced murine NTDs after calculating the toxicity using ADMETlab 3.0 and Deep-PK. We found that inositol supplementation ameliorated fetal neural phenotypes, crown-rump length, and body weight and rescued aberrant cell proliferation and dysregulated the GSK3β/β-catenin/CyclinD1 pathway in both animal and cellular models. The affinity of GSK3β-inositol interaction was analyzed and validated using molecular dynamics and surface plasmon resonance. GSK3β-edited cell models further revealed that inositol altered GSK3β post-transcriptional status and phosphorylation, consequently modulating the GSK3β/β-catenin/CyclinD1 signaling cascade. Overall, our study clarified that inositol alleviates lithium-induced NTDs via the GSK3β/β-catenin/CyclinD1 pathway, revealed the direct molecular interaction between inositol and GSK3β, and highlighted the potential of inositol as a therapeutic prevention against lithium-induced embryonic neurotoxicity for childbearing female BPD patients.
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BibTeX
@article{li2026inositoldependent,
title = {{Inositol-Dependent Alleviation of Lithium-Induced Embryonic Neurotoxicity in Mice Through the GSK3β/β-Catenin/CyclinD1 Pathway}},
author = {Shen Li and Jin Guo and Xiuwei Wang and Zhen Guan and Zhiqiang Zhu and Aiyun Yang and Jianhua Wang},
journal = {International Journal of Molecular Sciences},
year = {2026},
month = oct,
doi = {10.3390/ijms27219785},
url = {https://www.mdpi.com/1422-0067/27/21/9785},
note = {CC BY 4.0},
}
RIS
TY - JOUR
TI - Inositol-Dependent Alleviation of Lithium-Induced Embryonic Neurotoxicity in Mice Through the GSK3β/β-Catenin/CyclinD1 Pathway
AU - Shen Li
AU - Jin Guo
AU - Xiuwei Wang
AU - Zhen Guan
AU - Zhiqiang Zhu
AU - Aiyun Yang
AU - Jianhua Wang
PY - 2026
DA - 2026/10/30
JO - International Journal of Molecular Sciences
DO - 10.3390/ijms27219785
UR - https://www.mdpi.com/1422-0067/27/21/9785
AB - Lithium carbonate (Li2CO3) is a first-line pharmacotherapy for bipolar disorder (BPD) in female patients of childbearing age, although it is associated with embryonic teratogenicity. Lithium exposure in batteries and pharmaceuticals has been a toxicity factor for women’s reproductive health in energy, environment, and fitness fields. Neural tube defects (NTDs) are the severest reproductive outcome of maternal Li2CO3 exposure. Currently, there is a lack of effective prevention for Li2CO3 neurotoxicity. Our previous study revealed that lithium-induced murine NTDs correlated with enhanced proliferation and impaired inositol biosynthesis. In this study, 400 mg/kg inositol was used to treat the lithium-induced murine NTDs after calculating the toxicity using ADMETlab 3.0 and Deep-PK. We found that inositol supplementation ameliorated fetal neural phenotypes, crown-rump length, and body weight and rescued aberrant cell proliferation and dysregulated the GSK3β/β-catenin/CyclinD1 pathway in both animal and cellular models. The affinity of GSK3β-inositol interaction was analyzed and validated using molecular dynamics and surface plasmon resonance. GSK3β-edited cell models further revealed that inositol altered GSK3β post-transcriptional status and phosphorylation, consequently modulating the GSK3β/β-catenin/CyclinD1 signaling cascade. Overall, our study clarified that inositol alleviates lithium-induced NTDs via the GSK3β/β-catenin/CyclinD1 pathway, revealed the direct molecular interaction between inositol and GSK3β, and highlighted the potential of inositol as a therapeutic prevention against lithium-induced embryonic neurotoxicity for childbearing female BPD patients.
SN - 1422-0067
ER -