GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE335nnn/GSE335999/primaryOK200TranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE335999GEOGSEfalseBaicalein Ameliorates Diabetic Kidney Disease by Suppressing FN1-Mediated Extracellular Matrix Remodeling in Mesangial CellsDiabetic kidney disease (DKD) is the leading cause of end-stage renal disease worldwide, with its progression closely linked to aberrant extracellular matrix (ECM) accumulation and renal fibrosis that current therapies cannot adequately arrest. Using a reverse network pharmacology strategy, we integrated multiple human glomerular transcriptomic cohorts (GSE30528, GSE96804, GSE104948) and applied weighted gene co-expression network analysis (WGCNA) combined with 113 machine-learning model permutations to identify candidate hub genes; fibronectin 1 (FN1) ranked first among ECM-related features (mean |SHAP| = 0.182). Reverse network pharmacology subsequently identified baicalein as the candidate bioactive compound corresponding to FN1. Our own mouse single-cell RNA sequencing (3 DKD vs 3 control) demonstrated that Fn1 was predominantly expressed in mesangial cells and markedly upregulated in DKD compared with controls, with modest endothelial expression and near-negative signal in all other cell types. In vivo, db/db diabetic mice exhibited substantially elevated blood glucose (29.13 ± 1.60 vs 5.22 ± 0.24 mmol/L), serum creatinine (29.73 ± 2.21 vs 14.15 ± 1.32 µmol/L), and blood urea nitrogen (11.88 ± 0.81 vs 5.30 ± 0.43 mmol/L); baicalein intervention significantly reduced all three parameters and suppressed renal mRNA and protein expression of FN1, Collagen I, α-SMA, and TGF-β1, with histological improvements in glomerular mesangial expansion and interstitial fibrosis. Mesangial cell rescue experiments further showed that FN1 overexpression partially reversed the inhibitory effect of baicalein on high-glucose-induced ECM deposition and mesangial activation, indicating that FN1 functions as one contributing mediator of baicalein's anti-fibrotic action. Collectively, through multi-omics integration, animal modeling, and cell-level functional validation, this study reveals that baicalein ameliorates DKD by suppressing FN1-mediated ECM remodeling in mesangial cells, providing a candidate intervention node and potential natural therapeutic agent for DKD management.2026/09/30GSE335999GSM9824930GSM9824931GSM9824932GSM9824933GSM9824934GSM982493524247335999Mus musculus[42780336]