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.