Ethanol extract of Dysosma versipellis induces cytotoxicity in colonic epithelial cells via activation of the PI3K–Akt/MAPK signaling pathways

BACKGROUND: Dysosma versipellis (DV) has pharmacological activity but causes toxicity, especially in nontargeted tissues such as the colon. Understanding its underlying mechanism is crucial for safety. METHODS: UPLC-MS/MS was used to identify DV extract components. Active compounds (247) and targets (1901) were screened from databases; colon toxicity targets (1872) were obtained from GeneCards. The core targets were identified via network pharmacology and validated by molecular docking. The rats received DV extract for 5 days; the colon tissues were subjected to histopathology, transcriptomics, and metabolomics. Integrated omics was performed using KEGG/HMDB enrichment. RESULTS: Ten hub targets (GAPDH, AKT1, TP53, ACTB, TNF, IL6, ALB, EGFR, INS, and STAT3) were identified. 4'-Demethylpodophyllotoxin bound strongly to GAPDH/AKT1. KEGG revealed PI3K-Akt, lipid/atherosclerosis, and MAPK as the top enriched pathways. In vivo, DV damaged the colonic epithelium (shedding, bleeding). Transcriptomic analysis confirmed that PI3K-Akt/MAPK enrichment mediated cell death. Metabolomics revealed 414 differentially abundant metabolites, implicating amino sugar/nucleotide sugar metabolism. Integrated analysis highlighted shared disruptions in pancreatic secretion, protein digestion/absorption, and bile secretion. CONCLUSION: Oral DV metabolism releases 4'-demethylpodophyllotoxin, activating the PI3K-Akt/MAPK pathway in the colon epithelium and causing transcriptomic-metabolic dysregulation and epithelial necrosis. These findings inform clinical safety and detoxification strategies.