Renoprotective Role and Mechanisms of Luteolin in Chronic Kidney Disease: Insights From NHANES Data, Network Pharmacology, Mendelian Randomization, and Molecular Docking Techniques

ABSTRACT Although the renoprotective properties of flavonoids are well established in chronic kidney disease (CKD), further investigation is required to identify the most efficacious compound of flavonoids and to elucidate the underlying mechanisms. This study identified the most advantageous compound of flavonoids for CKD using data from the National Health and Nutrition Examination Survey (NHANES) database and investigated underlying mechanisms through mediation analysis, network pharmacology, bioinformatics analysis, Mendelian randomization (MR), and molecular docking techniques. Our research discovered that flavones, including luteolin and apigenin, played a crucial role in reducing the risk of CKD. The intake of apigenin, luteolin, and total flavones was all significantly associated with the risk reduction of CKD. We observed a nonlinear correlation between the luteolin intake and CKD risk, with the optimal daily intake identified as 1.36 mg. Then, we identified luteolin as the most important compound for kidney protection. Mediation effect analysis showed that luteolin might reduce CKD risk by regulating inflammation, serum uric acid, albumin, and bicarbonate. We identified 234 overlapping genes between luteolin and CKD, with enrichment analysis indicating their association with cellular metabolism, inflammation, oxidative stress, and immune responses. Additionally, we identified TP53, HSP90AA1, IL6, and ESR1 as the four hub genes, with HSP90AA1 identified as a risk target for CKD through MR analysis. Molecular docking techniques showed a strong binding affinity between luteolin and HSP90AA1. This study identified luteolin as a key flavonoid linked to lower CKD risk and suggested HSP90AA1 as a potential molecular target mediating its renoprotective effects.