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Mechanistic insights into PI3K/Akt-MMP9 signaling in Crotonis Fructus-induced reproductive toxicity via integrated
Qiaoxing Mou1, Zijian Zhang2, Xiaoyu Yan2
1School of Public Health, Chengdu University of Traditional Chinese Medicine, Chengdu, China.
Abstract:
Despite the widespread use of Crotonis Fructus (derived from Croton tiglium L.) in traditional medicine, its reproductive toxicity remains poorly characterized. Here, we investigated its potential mechanisms using Caenorhabditis elegans, network toxicology, molecular docking, and multi-model validation. Exposure to croton extract (CE) impaired reproductive capacity and shortened lifespan in C. elegans. Network toxicology identified 21 putative toxic compounds and 88 female reproductive dysfunction-related targets. Molecular docking revealed strong binding affinities of phorbol diesters, among others (key Crotonis Fructus components) to critical targets, including AKT1 and MMP9. In vitro (RAW264.7 cells) and in vivo (SD rats) experiments demonstrated CE-induced dysregulation of PI3K/Akt signaling pathway genes. Our findings establish that Crotonis Fructus induces female reproductive toxicity by regulating the release of inflammatory factors and activating the PI3K/Akt pathway, providing critical insights for refining its clinical safety guidelines.
Insights
Crotonis Fructus harms reproduction and lifespan in C. elegans. This study reveals its female reproductive toxicity mechanisms involving the PI3K/Akt pathway and inflammatory factors, crucial for safety guidelines.
Area of Science:
- Toxicology
- Pharmacology
- Reproductive Biology
Background:
- Crotonis Fructus (Croton tiglium L.) is used in traditional medicine.
- Its reproductive toxicity is not well understood.
Purpose of the Study:
- Investigate the mechanisms of Crotonis Fructus-induced reproductive toxicity.
- Validate findings across multiple models.
Main Methods:
- Utilized Caenorhabditis elegans models, network toxicology, and molecular docking.
- Performed in vitro (RAW264.7 cells) and in vivo (SD rats) experiments.
- Validated PI3K/Akt signaling pathway gene dysregulation.
Main Results:
- Croton extract (CE) impaired C. elegans reproductive capacity and lifespan.
- Identified 21 toxic compounds and 88 reproductive dysfunction targets.
- Phorbol diesters showed strong binding to AKT1 and MMP9.
- CE dysregulated PI3K/Akt pathway genes in vitro and in vivo.
Conclusions:
- Crotonis Fructus induces female reproductive toxicity.
- Mechanisms involve regulating inflammatory factors and activating the PI3K/Akt pathway.
- Findings inform clinical safety guidelines for Crotonis Fructus use.
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