Proteomic Profiling Demonstrates Reduced Cytotoxicity and Enhanced Bioactivity of Quercetin Oxidation Metabolites Relative to the Parent Compound

Quercetin (Q) is a widely consumed dietary flavonoid with multiple reported health benefits, yet its extremely low bioavailability—where circulating levels remain far below physiologically effective concentration raises controversy regarding its true biological relevance. Here, we systematically compared Q with its oxidative product, 2-(3,4-dihydroxybenzoyl)-2,4,6-trihydroxy-3(2H)-benzofuranone (BZF), naturally present in the dried outer layers of onions, to assess whether this conversion offers functional advantages. The results showed BZF displayed markedly superior antioxidant potential with improved solubility and enhanced cytoprotective effects. Proteomics revealed that BZF confers superior protection through dual regulation, simultaneously enhancing antioxidant defenses and suppressing pro-inflammatory signaling.