From Traditional Uses to Biochemical Evidence: Phytochemical Diversity and Bioactivities of Calotropis Gigantea-a Comprehensive Update Since 2013.

Calotropis gigantea has long been used in traditional medicine for the management of pain, inflammation, wounds, infections, and other disorders. This review critically updates the phytochemical and pharmacological evidence published from 2013 to 2026 by integrating compound-isolation studies, LC-MS/GC-MS profiling, activity-guided fractionation, mechanistic assays, and available safety data. Recent investigations have considerably expanded the chemical profile of C. gigantea, particularly its cardiac glycosides and cardenolides, together with triterpenoids, sterols, lignans, flavonoids, β-carboline alkaloids, and pyrrole derivatives. Studies of the latex, leaves, flowers, and root and stem bark consistently identify cardenolides as major contributors to biological potency. In vitro, several cardenolides exhibit nanomolar cytotoxicity against cancer cell lines and regulate HIF-1, Wnt/β-catenin, and Notch signaling, partly through Na+/K+-ATPase–Ca2+-associated mechanisms. Extracts, fractions, and isolated compounds also display antimicrobial, antioxidant, anti-inflammatory, wound-healing, anti-migraine, and organ-protective effects. These activities are supported by mechanistic findings involving oxidative stress, mitochondrial dysfunction, apoptosis, autophagy, and CYP450 modulation, the latter highlighting potential herb–drug interactions. In vivo findings provide preliminary support for several pharmacological effects, although translational evidence remains limited. The plant has also been applied in the green synthesis of Ag, ZnO, CuO, and MgO nanoparticles with additional biomedical properties. The novelty of this review lies in linking updated chemical evidence with potency-driving constituents, molecular mechanisms, safety considerations, and research gaps. Collectively, the findings establish C. gigantea as a valuable source of multi-target lead compounds while emphasizing the need for standardized quality markers, rigorous toxicological assessment, and well-designed preclinical and clinical studies.