Reduction in Liver Cancer Risk by Quercetin via Modulation of Urate Levels: Insights from Drug-Target Mendelian Randomization

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.