Multi-Omics and Functional Validation Identify a Quercetin-SLC15A2 Axis That Mediates the Anti-Fibrotic Effect of Shen-Kang Recipe in Diabetic Kidney Disease

  • Int J Mol Sci. 2026 Apr 5;27(7):3291. doi: 10.3390/ijms27073291.
Anna Zuo  1 ,  Shuyu Li  2 ,  Jiarun Xie  1 ,  Lishan Huang  3 ,  Ziwei Li  1 ,  Jingxin Lin  1 ,  Xiaoshan Zhao  1 ,  Ming Wang  1
Affiliations
  • 1. School of Traditional Chinese Medicine, Southern Medical University, Guangzhou 510515, China.
  • 2. Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China.
  • 3. School of Pharmacy, Jinan University, Guangzhou 510632, China.
PMID: 41977470 DOI: 10.3390/ijms27073291
Abstract

Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease. The Shen-Kang Recipe (SKR) is a traditional Chinese medicine formula used clinically to slow DKD progression, but its bioactive constituents and molecular targets remain unclear. Solute carrier family 15 member 2 (SLC15A2/PEPT2), a high-affinity peptide transporter expressed in renal proximal tubules, has been implicated in kidney pathophysiology, yet its potential role in mediating the therapeutic effects of the SKR has not been explored. Here, we evaluated the effects of the SKR in db/db mice and found that SKR treatment significantly improved renal function, attenuated glomerulosclerosis, and reduced interstitial Collagen deposition. Wide-target metabolomics and quantitative proteomics revealed that the SKR broadly reversed DKD-associated metabolic and proteomic disturbances, particularly in pathways related to energy and amino acid metabolism. Proteomic analysis identified SLC15A2 as a key proximal tubule protein downregulated in DKD and selectively restored by the SKR. UPLC-Q-TOF/MS-based serum pharmacochemistry and network pharmacology highlighted quercetin as a principal bioactive component of the SKR. Molecular docking, molecular dynamics simulations, and surface plasmon resonance (SPR) confirmed direct, high-affinity binding between quercetin and SLC15A2 (KD = 7.5 µM). In TGF-β1-stimulated HK-2 cells, quercetin suppressed epithelial-mesenchymal transition (EMT), as evidenced by restored E-cadherin and reduced N-Cadherin, vimentin, and α-SMA expression; this effect was abrogated by siRNA-mediated SLC15A2 knockdown, demonstrating the functional necessity of this axis. Collectively, these findings identify a quercetin-SLC15A2 axis through which the SKR inhibits EMT and alleviates renal fibrosis in DKD, providing a mechanistic basis for its clinical application and nominating SLC15A2 as a potential therapeutic target.

Keywords
SLC15A2; Shen-Kang Recipe; diabetic kidney disease; molecular dynamics simulations; multi-omics; quantitative proteomics; quercetin; renal fibrosis.
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