Summary: | <i>Houttuynia cordata</i> (<i>H. cordata</i>) is the most common herb as a food and traditional Chinese medicine. Currently, studies on its toxicity have mainly focused on hepatotoxicity. However, its potential embryotoxicity by long-term exposure is often overlooked. Objective: To investigate the effects of <i>H. cordata</i> on embryonic development and its toxicity mechanism by combining network pharmacology, molecular docking, and in vitro experimental methods. Methods: The effects of <i>H. cordata</i> on embryos were evaluated. Zebrafish embryos and embryoid bodies were administered to observe the effects of <i>H. cordata</i> on embryonic development. Based on network pharmacological analysis, it was found that the main active agents producing toxicity in <i>H. cordata</i> were oleanolic acid, lignan, and aristolactam AII. <i>H. cordata</i> can affect PI3K-Akt, MAPK, and Ras signaling pathways by regulating targets, such as AKT1, EGFR, CASP3, and IGF-1. RT-PCR and immunohistochemistry results showed that the expression of AKT1 and PI3K in the embryoid body was significantly reduced after drug administration (<i>p</i> < 0.05). Conclusions: The results of network pharmacology and in vitro experiments suggest that <i>H. cordata</i> may affect embryonic development by influencing the PI3K-Akt signaling pathway.
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