Cucurbitacins as multitarget pharmacological modulators: chemistry, biosynthesis, molecular targets, regulated cell death, and translational challenges, with emphasis on cucurbitacin B and I.

Cucurbitacins are highly oxidized tetracyclic triterpenoids with context-dependent pharmacological effects. This review focuses primarily on cucurbitacin B (CuB) and cucurbitacin I (CuI)-the most extensively characterized family members-while surveying the wider structural diversity of the cucurbitacin family. We integrate their chemistry, biosynthesis, and structure-activity relationships with structural interpretations of molecular target engagement and translational feasibility. We highlight how the electrophilic α,β-unsaturated ketone, C-17 side chain, acetylation, and glycosylation may influence potency and selectivity. Mechanistically, we evaluate Janus kinase 2/signal transducer and activator of transcription 3 signaling, ferroptosis involving solute carrier family 7 member 11 and glutathione peroxidase 4, PTEN-induced kinase 1-Parkin-dependent mitophagy, allosteric modulation of insulin-like growth factor 2 mRNA-binding protein 1, and NOD-like receptor family pyrin domain containing 3 inflammasome inhibition. We consider anti-inflammatory and hepatoprotective effects, tumor-associated macrophage repolarization, and sensitization to immune checkpoint blockade. Experimentally determined protein structures inform proposed covalent and allosteric interactions, but these models require direct target validation and biomarkers. We distinguish compound-specific findings from family-wide interpretations. Effects may vary with compound, dose, and disease context. By connecting these pathways to wax gourd genomic resources and synthetic-biology approaches, we consider opportunities for sustainable cucurbitacin production. However, low aqueous solubility, rapid clearance, hepatotoxicity, and a narrow therapeutic index constrain clinical translation. We assess nanoparticle formulations, solid dispersions, and structure-guided analog development as possible solutions. Distinct from cucurbitacin B-centered reviews, this synthesis integrates structural pharmacology, regulated cell death, immunomodulation, and biosynthetic engineering within a research roadmap prioritizing target validation, biomarkers, and preclinical assessment.