Mechanistic anticancer effects of melittin across cancer hallmarks: A narrative evidence synthesis

Venoms are complex natural secretions that contain bioactive molecules with diverse pharmacological effects. Melittin, a 26-amino-acid amphipathic peptide derived from the venom of the honeybee Apis mellifera, has been widely reported to exert cytotoxic effects in cancer models. Although melittin is best known for its membrane-disruptive and haemolytic properties, increasing evidence suggests that it also modulates intracellular signalling pathways involved in cancer progression. This review synthesised evidence on the mechanistic effects of melittin in cancer-related pathways. Articles were retrieved from PubMed, Ovid MEDLINE, and Scopus using the search terms "melittin," "mechanism," and "cancer." A total of 454 records were identified. After duplicate removal and staged screening, 64 studies were included in the final synthesis. Mechanistic findings were organised according to cancer hallmark-related processes, including hypoxia-associated signalling, proliferative and survival signalling, apoptosis, cell-cycle progression, Wnt/β-catenin signalling, epithelial-mesenchymal transition, membrane disruption, and calmodulin-related mechanisms. The most consistently supported effects of melittin involved induction of apoptosis, suppression of PI3K/AKT/mTOR and MAPK/ERK signalling, inhibition of HIF-1α/VEGF-associated hypoxic and angiogenic responses, and direct membrane permeabilisation. Evidence for Wnt/β-catenin modulation, cyclin-CDK-mediated cell-cycle arrest, and suppression of EMT-associated invasive phenotypes was promising but more context-dependent. Calmodulin-related mechanisms remain plausible but insufficiently validated in contemporary cancer models. Melittin demonstrates multi-targeted anticancer activity across preclinical models, but its development is constrained by haemolytic activity, off-target cytolysis, poor oral bioavailability, and uncertain tumour selectivity. Future studies should define mechanism-exposure relationships, distinguish regulated pathway modulation from secondary cytotoxic stress responses, and prioritise targeted delivery, therapeutic index assessment, and rational sequence optimisation.