J Ethnopharmacol. 2026 May 15:121861. doi: 10.1016/j.jep.2026.121861. Online ahead of print.
ABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: EUPHORBIAE EBRACTEOLATAE RADIX (Langdu), the dried root of Euphorbia fischeriana Steud. (E. fischeriana), has been widely used in Mongolian and traditional Chinese medicine for the treatment of inflammatory disorders and malignancies. However, its clinical application is limited by its gastrointestinal toxicity. Milk processing is traditionally used to reduce toxicity, but the underlying mechanisms remain unclear.
AIM OF THE STUDY: To investigate the mechanisms underlying E. fischeriana-induced intestinal toxicity and to evaluate the effects of traditional milk processing.
MATERIALS AND METHODS: Zebrafish and mouse models were used to assess intestinal alterations induced by E. fischeriana extract. Transcriptomic and metabolomic analyses were performed to characterize molecular changes. Barrier integrity was evaluated by tight junction gene expression and organoid permeability assays. Circadian rhythmicity was analyzed in HT-29 cells synchronized with dexamethasone.
RESULTS: Exposure to the extract of raw E. fischeriana (EEF) accelerated gastrointestinal transit in zebrafish and induced villus shortening and epithelial disorganization. Multi-omics analysis revealed profound metabolic reprogramming, including suppression of mitochondrial energy and lipid metabolism, together with perturbation of nitrogen-related pathways, accompanied by circadian disruption and epithelial remodeling. Functionally, EEF reduced Per3 oscillatory amplitude and downregulated tight junction genes (Cldn3, Cldn4, and Cldn15), leading to increased epithelial permeability. Conversely, the extract of milk-processed E. fischeriana (EPEF) partially alleviated intestinal structural damage and restored metabolic pathways, but circadian rhythmicity remained incompletely recovered.
CONCLUSIONS: E. fischeriana disrupts intestinal metabolic and circadian coordination, leading to epithelial barrier dysfunction. Milk processing partially mitigates intestinal metabolic disturbance and structural injury, but fails to fully restore circadian regulation. These findings provide mechanistic insight into the intestinal toxicity of E. fischeriana and the detoxification mechanism of traditional milk processing.
PMID:42142552 | DOI:10.1016/j.jep.2026.121861