Valorization of Sardinian Grapevine Leaves as a Sustainable Source of Flavonols with Anticancer Potential

Grapevine (Vitis vinifera L.) leaves are an abundant agricultural by-product and an underexploited source of bioactive polyphenols. This study characterized hydroalcoholic leaf extracts from autochthonous Sardinian cultivars and evaluated their effects in RKO human colorectal carcinoma cells. LC–HRMS revealed flavonol-rich profiles dominated by glycosylated derivatives of quercetin, kaempferol, and isorhamnetin, with marked cultivar-dependent differences and higher total flavonol abundance in Cannonau and Nieddera. Cyclic voltammetry showed distinct redox reactivity among extracts, with Vermentino and Martellada Bianca displaying the strongest electrochemical responses, consistent with their modulation of intracellular reactive oxygen species. In RKO cells, the extracts reduced metabolic activity in a dose-dependent manner, with IC50 values ranging from 100.3 to 251.8 µg/mL. At the molecular level, treatments modulated c-myb expression and shifted the bax/bcl2 balance toward a pro-apoptotic profile. These effects were supported by DAPI staining, showing chromatin condensation and nuclear fragmentation, and by moderate activation of caspase-3/7. Overall, Sardinian grapevine leaf extracts showed cultivar-specific phenolic composition, redox activity, and pro-apoptotic effects in an in vitro colorectal cancer model, supporting their potential valorization as sustainable sources of bioactive compounds. Further studies addressing bioavailability, metabolism, and in vivo effects are required to assess their physiological relevance and translational potential.