2. Academic Validation
  3. The natural compound stachyose targets SGLT2-mediated metabolic reprogramming to ameliorate diabetic kidney disease

The natural compound stachyose targets SGLT2-mediated metabolic reprogramming to ameliorate diabetic kidney disease

  • Phytomedicine. 2025 Aug 19:147:157182. doi: 10.1016/j.phymed.2025.157182.
Yicai Wu 1,  Yun Cao 2,  Ling Feng 3,  Yu Yan 3,  Huiluan Ye 4,  Kaiyue Tang 3,  Yanzhen Wei 3,  Ting Chen 3,  Xiaohua Guo 3,  Yiqiong Ma 5
Affiliations

Affiliations

  • 1 Department of Nephrology, Ganzhou People's Hospital, No.17, Hongqi Avenue, Zhanggong District, Ganzhou City, 341000, Jiangxi Province, China.
  • 2 Department of Nephrology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou,100053, China.
  • 3 Department of Nephrology, Shenzhen Hospital, Southern Medical University (Shenzhen School of Clinical Medicine, Southern Medical University), Xinhu Rd13#, Shenzhen, 518101, China.
  • 4 The Second Clinical Medical College, Southern Medical University, Shatai South Rd1023-1063#, Guangzhou, 510515, China.
  • 5 Department of Nephrology, Shenzhen Hospital, Southern Medical University (Shenzhen School of Clinical Medicine, Southern Medical University), Xinhu Rd13#, Shenzhen, 518101, China. Electronic address: yiqiongma@smu.edu.cn.
PMID: 40848672 DOI: 10.1016/j.phymed.2025.157182
Abstract

Background: Diabetic kidney disease (DKD) is a leading cause of end-stage renal disease with no curative treatment currently available. Aberrant metabolic reprogramming in renal tubular epithelial cells contributes to renal fibrosis in DKD. Sodium-glucose cotransporter-2 (SGLT2) is upregulated in DKD and plays a central role in promoting metabolic dysfunction.

Purpose: To identify and validate a natural compound that targets SGLT2-mediated metabolic reprogramming and attenuates renal fibrosis in DKD.

Study design: This study employed in silico compound screening, in vitro assays, and multiple in vivo DKD models (db/db and HFD/STZ mice), including CRISPR-Cas9 SGLT2 knockout models and SGLT2-TYR270 point mutations, to assess the efficacy and mechanism of the candidate compound stachyose.

Methods: A natural product library of 4600 compounds was screened against the SGLT2 protein using molecular docking. The top hits were validated via cellular thermal shift and proteolysis assays in high-glucose-treated human primary tubular epithelial cells. Efficacy of stachyose was evaluated in DKD mouse models by assessing renal function, fibrosis, metabolic markers, and mitochondrial function. Mechanistic studies included molecular dynamics simulation, AMPK pathway analysis, and SPR binding kinetics.

Results: Stachyose bound SGLT2 with high affinity at the Tyr270 site, promoting its degradation and reversing metabolic reprogramming. In vitro, stachyose restored fatty acid oxidation, suppressed glycolysis, reduced lipid accumulation, and improved mitochondrial function in tubular cells. In vivo, stachyose improved renal function and attenuated fibrosis in both DKD models. These effects were abolished in SGLT2-knockout and Tyr270-mutant mice, confirming the specificity of action.

Conclusion: Stachyose is a first-in-class natural SGLT2 destabilizer that ameliorates DKD progression by reversing metabolic reprogramming in tubular epithelial cells. It represents a promising therapeutic strategy for DKD with potential advantages over existing SGLT2 inhibitors.

Keywords

Diabetic kidney disease; Metabolic reprogramming; Renal fibrosis; SGLT2; Stachyose.

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