Bioactive plant and fungal metabolites show anticancer activities in preclinical oral cancer models

Oral cancer remains a major global health burden. Current therapies are often limited by recurrence, drug resistance, and systemic toxicity. Natural bioactive metabolites, particularly those derived from medicinal plants used in Traditional Chinese Medicine are increasingly investigated as multitarget anticancer leads. In this review, we integrated evidence from studies published between January 2010 and June 2025. We summarize representative flavonoids, terpenoids, phenolic metabolites, alkaloids, polysaccharides, and quinones evaluated in oral cancer models. Reported activities include suppression of proliferation, induction of apoptosis and autophagy, inhibition of epithelial–mesenchymal transition and angiogenesis, and modulation of tumor metabolism and immune pathways. However, the current evidence base remains largely preclinical and frequently relies on simplified in vitro assays. Pharmacokinetic bridging, toxicity evaluation, and clinically relevant validation are still limited. Importantly, several polyphenolic metabolites exhibit pan-assay interference (PAINS) liabilities, requiring cautious interpretation of pathway-level findings. Advances in nano-delivery systems, rational structural optimization, and combination strategies may improve exposure and selectivity. Future work should emphasize PAINS-aware pharmacological rigor, orthogonal target validation, advanced translational models, and biomarker-driven clinical trials to support the development of genuinely druggable natural metabolite candidates for oral cancer management.