Most studies on the antioxidant activity of flavonoids like Quercetin (Q) do not consider that it comprises a series of sequential reactions. Therefore, the present study examines how the redox energy flows through the molecule during Q’s antioxidant activity, by combining experimental data with quantum calculations. It appears that several main pathways are possible. Pivotal are subsequently: deprotonation of the 7-OH group; intramolecular hydrogen transfer from the 3-OH group to the 4-Oxygen atom; electron transfer leading to two conformers of the Q radical; deprotonation of the OH groups in the B-ring, leading to three different deprotonated Q radicals; and finally electron transfer of each deprotonated Q radical to form the corresponding quercetin quinones. The quinone in which the carbonyl groups are the most separated has the lowest energy content, and is the most abundant quinone. The pathways are also intertwined. The calculations show that Q can pick up redox energy at various sites of the molecule which explains Q’s ability to scavenge all sorts of reactive oxidizing species. In the described pathways, Q picked up, e.g., two hydroxyl radicals, which can be processed and softened by forming quercetin quinone.

In the antioxidant activity of quercetin (Q), stabilization of the energy in the quercetin radical (Q^•) by delocalization of the unpaired electron (UE) in Q^• is pivotal. The aim of this study is to further examine the delocalization of the UE in Q^•, and to elucidate the importance of the functional groups of Q for the stabilization of the UE by combining experimentally obtained spin resonance spectroscopy (ESR) measurements with theoretical density functional theory (DFT) calculations. The ESR spectrum and DFT calculation of Q^• and structurally related radicals both suggest that the UE of Q^• is mostly delocalized in the B ring and partly on the AC ring. The negatively charged oxygen groups in the B ring (3′ and 4′) of Q^• have an electron-donating effect that attract and stabilize the UE in the B ring. Radicals structurally related to Q^• indicate that the negatively charged oxygen at 4′ has more of an effect on concentrating the UE in ring B than the negatively charged oxygen at 3′. The DFT calculation showed that an OH group at the 3-position of the AC ring is essential for concentrating the radical on the C2–C3 double bond. All these effects help to explain how the high energy of the UE is captured and a stable Q^• is generated, which is pivotal in the antioxidant activity of Q.

Quercetin, a dietary flavonoid, has demonstrated antioxidant, anti-inflammatory, and anti-tumor activities. Increasing evidence highlights that its metabolites contribute to these health benefits. This review summarizes current knowledge on the molecular mechanisms and therapeutic potential of quercetin and its metabolites in non-alcoholic fatty liver disease (NAFLD) and hepatocellular carcinoma (HCC), with a focus on redox modulation and microbiota interactions. Substantial preclinical evidence supports the protective effects of quercetin and its metabolites in NAFLD and HCC. However, clinical translation is hampered by poor bioavailability, potential redox–drug interactions, and incomplete understanding of the precise molecular mechanisms involved. Future research should prioritize further elucidating the molecular mechanisms, as they represent the foundation for the rational use of quercetin and metabolite-based derivatives in the prevention and treatment of liver-related diseases. In particular, strategies that direct the activity of these bioactive compounds to their desired sites of action—by exploiting differences between normal and cancer cells—warrant more in-depth investigation.

It has been reported that in an oxidative environment, the flavonoid 2R,3R-dihydroquercetin (2R,3R-DHQ) oxidizes into a product that rearranges to form quercetin. As quercetin is a very potent antioxidant, much better than 2R,3R-DHQ, this would be an intriguing form of targeting the antioxidant quercetin. The aim of the present study is to further elaborate on this targeting. We can confirm the previous observation that 2R,3R-DHQ is oxidized by horseradish peroxidase (HRP), with H₂O₂ as the oxidant. However, HPLC analysis revealed that no quercetin was formed, but instead an unstable oxidation product. The inclusion of glutathione (GSH) during the oxidation process resulted in the formation of a 2R,3R-DHQ-GSH adduct, as was identified using HPLC with IT-TOF/MS detection. GSH adducts appeared on the B-ring of the 2R,3R-DHQ quinone, indicating that during oxidation, the B-ring is oxidized from a catechol to form a quinone group. Ascorbate could reduce the quinone back to 2R,3R-DHQ. No 2S,3R-DHQ was detected after the reduction by ascorbate, indicating that a possible epimerization of 2R,3R-DHQ quinone to 2S,3R-DHQ quinone does not occur. The fact that no epimerization of the oxidized product of 2R,3R-DHQ is observed, and that GSH adducts the oxidized product of 2R,3R-DHQ on the B-ring, led us to conclude that the redox-modulating activity of 2R,3R-DHQ quinone resides in its B-ring. This could be confirmed by chemical calculation. Apparently, the administration of 2R,3R-DHQ in an oxidative environment does not result in ‘biotargeting’ quercetin.

Background: Quercetin, a dietary flavonoid and a widely used supplement, has hepatoprotective properties. Given its urate-lowering effects and epidemiological evidence linking elevated serum urate levels to liver cancer risk, we tested whether quercetin reduces liver cancer risk via modulation of urate levels by bioinformatics methods. Methods: We employed drug-target Mendelian randomization using genome-wide association study summary statistics from public databases (e.g., MRC-IEU) to assess genetic associations, and integrated these findings with GEO datasets (such as GSE138709 and GSE179443) and immune infiltration analyses using tools like xCell, TIMER. Results: Our analyses identified ABCG2-mediated urate elevation as a causal risk factor for hepatocellular carcinoma (OR = 1.001, p < 0.01), cholangiocarcinoma (OR = 3.424, p < 0.01), and liver fibrosis (OR = 2.528, p < 0.01). Single-cell transcriptomics revealed elevated ABCG2 expression in cholangiocarcinoma endothelial cells, while immune infiltration analysis showed significant associations between ABCG2 expression and both endothelial cell and macrophage infiltration. Survival analysis further indicated that ABCG2 was not associated with poor prognosis in cholangiocarcinoma or hepatocellular carcinoma. Conclusions: Considering quercetin’s multifaceted interactions with BCRP/ABCG2, our findings support its potential use as a preventive dietary supplement for hepatic diseases rather than as an adjunctive therapy for established liver cancer.

Aspergillus flavus is both an agricultural and clinical pathogen, notable for its ability to contaminate crops with aflatoxins and cause invasive aspergillosis. The increasing emergence of azole resistance in A. flavus poses a serious challenge to food safety and human health. Although mutations in ergosterol biosynthesis genes have been reported in resistant isolates, their functional contributions remain largely unvalidated. In this study, we investigated the role of the CYP51A Y119F mutation in azole resistance. Site-directed mutants were generated using PCR-based gene editing, and their susceptibility to antifungal agents was assessed through Clinical and Laboratory Standards Institute broth microdilution and agar diffusion assays. The Y119F mutation reduced susceptibility specifically to voriconazole and isavuconazole, while susceptibility to itraconazole and posaconazole remained unchanged. To explore the structural basis of this phenotype, molecular dynamics simulations were performed. The mutant protein exhibited greater fluctuations and reduced conformational stability compared to the wild-type enzyme. Tunnel analysis further indicated that the Y119F substitution caused narrowing and shortening of the main access tunnels to the heme-binding pocket, likely impairing azole access and binding. The combined biochemical and structural analyses suggest that Y119F represents a primary resistance-conferring mutation that modifies the structural dynamics of CYP51A.