Baicalein attenuates extracellular matrix remodeling via FN1 in diabetic kidney disease: a multi-omics, machine-learning and mesangial-cell rescue study.

Authors

Yimin Li, Yuqing Tian, Zhenhua Wu, Fangyu Xia, Liyifan Zheng, Meifang Ren, Meijiao Zhao, Qian Zhang, Jinchuan Tan, Qingyou Xu, Fengwen Yang

Published in

Frontiers in pharmacology. Volume 17. Pages 1852694. Epub Sep 09, 2026.

Abstract

Three transcriptomic cohorts, GSE30528, GSE96804, and GSE104948, comprising 62 DKD and 59 control samples, were integrated for differential expression and weighted gene co-expression network analyses. Candidate genes were prioritized using disease databases, protein-protein interaction analysis, 113 machine-learning algorithm combinations, and SHAP analysis. Model performance was evaluated in GSE30529 and GSE99339. The prioritized genes were then subjected to reverse network pharmacology, followed by FN1 validation in GSE47184 and surface plasmon resonance (SPR). An independently generated mouse single-cell RNA-sequencing dataset comprising 36,819 cells from three DKD and three control mice was subsequently used to localize Fn1 expression. Finally, db/db mouse experiments and an Fn1-overexpression rescue experiment in high-glucose-treated mesangial cells were performed.
We identified 441 differentially expressed genes, including 197 upregulated and 244 downregulated genes. Intersection analysis yielded 94 candidate genes. The blue WGCNA module contained 1,346 genes and was positively correlated with DKD (r = 0.59, P = 1 × 10-12). The glmBoost model achieved the highest mean area under the receiver operating characteristic curve (0.938), and SHAP analysis prioritized FN1, COL1A2, VCAN, FBN1, and COL4A1. Reverse network pharmacology mapped baicalein only to FN1. GSE47184 independently confirmed the direction of FN1 upregulation in DKD. SPR detected a concentration-dependent interaction between baicalein and immobilized recombinant human FN1, with an apparent KD of 8.04 × 10-5 M. Single-cell analysis localized Fn1 expression to mesangial cells, and subsequent mouse-level pseudobulk analysis showed increased mesangial Fn1 expression in DKD mice. Baicalein reduced serum creatinine and blood urea nitrogen levels, ameliorated renal histopathological injury, and decreased fibronectin and other fibrosis-associated molecules in db/db mice. In mesangial cells, Fn1 overexpression aggravated the high-glucose-induced profibrotic molecular phenotype and partially attenuated the inhibitory effects of baicalein on ECM-associated molecular changes.
Baicalein attenuated renal injury and ECM remodeling in experimental DKD. FN1 was functionally involved in the profibrotic phenotype and the cellular response to baicalein.

PMID:
42780336
Bibliographic data and abstract were imported from PubMed on 24 Sep 2026.

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