Cucurbitacin B in cancer: A comprehensive review of its targets and molecular mechanisms

Cancer remains a leading cause of mortality in industrialized nations, driving ongoing research efforts to develop more effective and less toxic therapeutic approaches. Cucurbitacin B (CuB), a tetracyclic triterpene compound abundant in Cucurbitaceae family plants, has garnered significant attention in recent years because of its promising therapeutic properties. This review has synthesized current evidence elucidating CuB's molecular targets and associated anticancer mechanisms. Our analysis delineates 18 targets of CuB, categorized by their interaction modality: covalent binding partners (IGF2BP1, GRP78, PCK2, MTCH2) and non-covalent interactors, including transcription factors (STAT3, Notch1), transferases (Src, PI3K, AKT, mTOR, RAF, MEK, ERK), chaperone (Mortalin), anti-oncogene (p53), ligase (HDM2), RNA-binding protein (hnRNP-K), and immune system receptor (TLR4). Numerous in vitro and in vivo studies have demonstrated that CuB exerts its anticancer effects through diverse mechanisms, including the inhibition of cell proliferation, metastasis and angiogenesis, as well as the induction of cytoskeleton disruption, cell cycle arrest, DNA damage, apoptosis, autophagy, ferroptosis, pyroptosis and epigenetic regulation. Moreover, CuB improves tumor resistance and has synergistic anticancer effects with chemotherapy drugs. This comprehensive target landscape analysis provides a mechanistic framework for developing CuB-based combination therapies and structure-optimized derivatives, which promote the development of innovative and effective cancer treatment strategies.