Acute toxicity assessment and metabolomic profiling of Taxus sumatrana leaf extract as a sustainable alternative to bark harvesting

Taxus sumatrana (Taxaceae) is an Indonesian endemic species known for its anticancer activity due to taxane derivatives. Despite its pharmacological importance, T. sumatrana remains underexplored, and its populations are increasingly threatened by extensive bark harvesting, compromising the tree’s natural defence system and often leads to stem rot and mortality. This risk is increasing since the species has slow generative and vegetative growth. The use of regenerable plant parts, such as leaves, represents a more sustainable alternative. This study aimed to evaluate the in vivo acute oral toxicity of ethanolic T. sumatrana leaf extract in mice to support its safe and sustainable utilization. Metabolomic profiling was also conducted using UPLC-HRMS/MS, followed by in silico toxicity prediction. In vivo evaluation included mortality observation, relative organ-to-body weight ratio analysis, blood chemistry assessment, and histopathological examination. No mortality was observed within 24 h of administration, indicating an LD₅₀ greater than 2000 mg/kgBW. In silico toxicity prediction showed that all 100 identified metabolites were predominantly non-AMES toxic, non-inhibitors of hERG I/II channels, and had predicted acute LD₅₀ values exceeding 2000 mg/kgBW. Relative organ weights and blood chemistry parameters exhibited only minor variations across treatment groups, reflecting a favourable physiological response. Histopathological evaluation revealed liver and kidney abnormalities below 20%, indicating minimal and tolerable tissue alterations. These findings support the use of leaves as a safe and sustainable alternative to bark harvesting. Further toxicity studies particularly sub-chronic and chronic toxicity evaluations are recommended to reach a comprehensive conclusion on the safe use of the leaf extract.