Bergamottin: a multitarget natural furanocoumarin with promising anticancer potential

Bergamottin, a natural furanocoumarin derived from Citrus species, exhibits broad-spectrum antitumor activity by targeting key oncogenic pathways and overcoming therapeutic resistance. This review synthesizes its physicochemical properties, metabolic behavior, and mechanisms of action across diverse malignancies, including leukemia, breast cancer, lung cancer, hepatocellular carcinoma, gliomas, and colorectal cancer. Bergamottin exerts its anticancer effects through a hierarchical regulatory network: at the primary level, it directly inhibits P-glycoprotein (P-gp) and cytochrome P450 (CYP) enzymes, thereby reversing multidrug resistance and altering drug metabolism; at the secondary level, it suppresses oncogenic signaling cascades including signal transducer and activator of transcription 3 (STAT3), phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR), and rat sarcoma virus/rapidly accelerated fibrosarcoma/extracellular signal-regulated kinase (Ras/Raf/ERK); ultimately, these actions converge on apoptosis induction, cell cycle arrest, and metastasis inhibition. Preclinical studies demonstrate its ability to enhance chemotherapy efficacy via improved bioavailability and metabolic suppression. Additionally, it induces apoptosis, arrests cell cycle progression, and suppresses metastasis through epithelial-mesenchymal transition (EMT) inhibition and Ras-related C3 botulinum toxin substrate 1 (Rac1)/matrix metalloproteinase-9 (MMP-9) axis regulation. Despite its promise, challenges like pharmacokinetic variability, genotoxicity of metabolites, and limited clinical data necessitate further investigation. While preclinical evidence supports bergamottin's potential as a multi-target chemosensitizer, its standalone antitumor efficacy remains modest and its safety profile incompletely characterized. Future research must prioritize systematic toxicity profiling and cautious preclinical evaluation before any translational attempt.