Vicenin-2 alleviates oxidative stress in HT22 cells and Caenorhabditis elegans as a potential KEAP1-NRF2 interaction inhibitor.

Flavone C-glycosides are a class of compounds characterized by glycosyl moieties directly bonded to the flavone skeleton via CC linkages, predominantly on the C-6 and C-8 positions of the A-ring. Vicenin-2, a 6,8-di-C-glycoside derived from apigenin, is widely present in some dietary sources such as juice, herbal teas and stewed soups. While its antioxidant potential is recognized, the molecular mechanisms underlying its protective effects against oxidative stress remain poorly explored. Given the vicious cycle between oxidative stress and neurotoxicity, this study investigated the protective efficacy and molecular mechanisms of vicenin-2 against t-Butyl Hydroperoxide (tBHP)-challenged Caenorhabditis elegans and H₂O₂-induced HT22 neuronal cells. Molecular docking and dynamics simulation revealed that vicenin-2 disrupts the binding of KEAP1 and NRF2. Both in vitro and in vivo assay demonstrated treatment of vicenin-2 activated the antioxidant system, and qPCR and Western blot results confirmed the KEAP1-NRF2-HO-1 pathway as central to its activities. Computational-experimental synergy unveils vicenin-2 as a KEAP1-NRF2 protein-protein interaction inhibitor. Our findings highlight the potential of vicenin-2 for oxidative stress conditions, and position vicenin-2 as a promising neuroprotective therapeutic candidate although more mammal experimental evidence is warranted.