Wu Yicai, Cao Yun, Feng Ling, Yan Yu, Ye Huiluan, Tang Kaiyue, Wei Yanzhen, Chen Ting, Guo Xiaohua, Ma Yiqiong
Department of Nephrology, Ganzhou People's Hospital, No.17, Hongqi Avenue, Zhanggong District, Ganzhou City, 341000, Jiangxi Province, China.
Department of Nephrology, Hainan General Hospital (Hainan Affiliated Hospital of Hainan Medical University), Haikou,100053, China.
Phytomedicine. 2025 Nov;147:157182. doi: 10.1016/j.phymed.2025.157182. Epub 2025 Aug 19.
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.
To identify and validate a natural compound that targets SGLT2-mediated metabolic reprogramming and attenuates renal fibrosis in DKD.
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.
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.
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.
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.
糖尿病肾病（DKD）是终末期肾病的主要病因，目前尚无治愈方法。肾小管上皮细胞中异常的代谢重编程导致DKD中的肾纤维化。钠-葡萄糖协同转运蛋白2（SGLT2）在DKD中上调，并在促进代谢功能障碍中起核心作用。
鉴定并验证一种靶向SGLT2介导的代谢重编程并减轻DKD中肾纤维化的天然化合物。
本研究采用计算机化合物筛选、体外试验以及多种体内DKD模型（db/db和高脂饮食/链脲佐菌素诱导的小鼠），包括CRISPR-Cas9 SGLT2基因敲除模型和SGLT2-TYR270点突变模型，以评估候选化合物水苏糖的疗效和机制。
使用分子对接技术针对SGLT2蛋白筛选了一个包含4600种化合物的天然产物文库。通过细胞热迁移和蛋白酶解试验在高糖处理的人原代肾小管上皮细胞中验证了筛选出的最佳化合物。通过评估肾功能、纤维化、代谢标志物和线粒体功能，在DKD小鼠模型中评估了水苏糖的疗效。机制研究包括分子动力学模拟、AMPK途径分析和表面等离子体共振结合动力学。
水苏糖在Tyr270位点与SGLT2高亲和力结合，促进其降解并逆转代谢重编程。在体外，水苏糖恢复了脂肪酸氧化，抑制了糖酵解，减少了脂质积累，并改善了肾小管细胞中的线粒体功能。在体内，水苏糖改善了两种DKD模型的肾功能并减轻了纤维化。在SGLT2基因敲除和Tyr270突变小鼠中这些作用消失，证实了作用的特异性。
水苏糖是首个天然的SGLT2去稳定剂，通过逆转肾小管上皮细胞中的代谢重编程改善DKD进展。它代表了一种有前景的DKD治疗策略，相对于现有的SGLT2抑制剂具有潜在优势。
