尿石素A激活PI3K/AKT通路抑制高糖高脂介导的脂肪间充质干细胞铁死亡

doi:10.7506/spkx1002-6630-20250512-060

食品科学 ›› 2025, Vol. 46 ›› Issue (21): 180-189.doi: 10.7506/spkx1002-6630-20250512-060

• 营养卫生 • 上一篇

尿石素A激活PI3K/AKT通路抑制高糖高脂介导的脂肪间充质干细胞铁死亡

周克春，李包娟，王若彤，张䶮之

（1.新疆医科大学药学院，新疆?乌鲁木齐 830000；2.新疆天然药物活性组分与释药技术重点实验室，新疆?乌鲁木齐 830000）

发布日期:2025-11-10
基金资助:
国家自然科学基金地区科学基金项目（82560727）；新疆天然药物活性组分与释药技术重点实验室开放课题（2024XJTRZ03）；新疆地区高发疾病研究教育部重点实验室开放课题（2024A02）

Urolithin A Inhibits Ferroptosis Induced by High Glucose and Palmitic Acid in Adipose-Derived Mesenchymal Stem Cells by Activating the PI3K/AKT Pathway

ZHOU Kechun, LI Baojuan, WANG Ruotong, ZHANG Yanzhi

(1. School of Pharmacy, Xinjiang Medical University, ürümqi 830000, China; 2. Key Laboratory of Xinjiang Active Components of Natural Medicines and Drug Release Technology, ürümqi 830000, China)

Published:2025-11-10

摘要/Abstract

摘要： 目的：探究尿石素A（urolithin A，UA）对高糖高脂微环境下脂肪间充质干细胞（adipose-derived mesenchymal stem cells，ADMSCs）铁死亡的影响及机制。方法：25 mmol/L葡萄糖联合0.25 mmol/L棕榈酸模拟糖尿病环境，诱导ADMSCs细胞损伤，通过CCK-8法检测UA干预后ADMSCs活力；丙二醛、谷胱甘肽、Fe2＋试剂盒分别检测铁死亡标志物含量。数据库获得UA、2型糖尿病及铁死亡相关靶点，交集靶点导入STRING数据库和Cytoscape 3.9.1构建蛋白互作，DAVID 6.8数据平台对交集靶点进行信号通路富集，利用AutoDock Tools 1.5.7及PyMOL进行分子对接，预测UA及核心靶点结合能。免疫蛋白印迹法（western blot，WB）检测铁死亡相关蛋白及磷脂酰肌醇3-激酶/蛋白激酶B（phosphoinositide 3-kinase/protein kinase B，PI3K/AKT）通路蛋白表达水平。结果：分离的ADMSCs表面表达CD29、CD90，不表达CD11b、CD45，具有多项分化潜能。在体外高糖高脂模拟糖尿病环境下ADMSCs被损伤，UA干预后显著增强ADMSCs活力，铁死亡标记物谷胱甘肽含量显著升高，丙二醛和Fe2＋含量降低。网络药理学共筛选出54 个UA、2型糖尿病、铁死亡交集靶点，京都基因与基因组百科全书显示UA可能通过PI3K/AKT通路调控ADMSCs铁死亡，分子对接显示UA能与关键蛋白稳定结合。WB结果显示UA干预可增加高糖高脂损伤ADMSCs细胞中谷胱甘肽过氧化物酶4（glutathione peroxidase 4，GPX4）、p-AKT、p-PI3K表达量，减少长链酰基辅酶A合成酶4（long-chain acyl-CoA synthetase 4，ACSL4）表达量。结论：UA能逆转高糖高脂模拟糖尿病环境下ADMSCs细胞铁死亡，其机制可能是通过激活PI3K/AKT调控下游铁死亡GPX4/ACSL4通路。

关键词: 尿石素A；高糖高脂；脂肪间充质干细胞；铁死亡；磷脂酰肌醇3-激酶/蛋白激酶B

Abstract: Objective: To explore the inhibitory effect and mechanism of urolithin A (UA) on ferroptosis in adipose-derived mesenchymal stem cells (ADMSCs) under a high-glucose high-palmitic acid environment. Methods: The diabetic environment was simulated using a combination of 25 mmol/L glucose and 0.25 mmol/L palmitic acid to induce damage to ADMSCs, and cell viability was detected by the CCK-8 method after UA intervention. The ferroptosis markers malondialdehyde (MDA), glutathione, and ferrous ion were detected. Targets related to UA, type 2 diabetes mellitus and ferroptosis were obtained from online databases and the intersection targets were imported into the STRING database and the Cytoscape 3.9.1 software to construct a protein-protein interaction (PPI) network. The DAVID 6.8 data platform was used to perform signaling pathway enrichment analysis on the intersection targets, and AutoDock Tools 1.5.7 and PyMOL were employed for molecular docking to predict the binding energies between UA and core targets. Western blot (WB) was used to detect the expression of proteins associated with ferroptosis and the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Results: The isolated ADMSCs expressed CD29 and CD90 but not CD11b or CD45 on their surface and had multilineage differentiation capacity. In vitro, ADMSCs were injured under the simulated diabetic condition. The viability was significantly enhanced after UA intervention. In addition, the content of glutathione was significantly increased, while the content of MDA and ferrous ion was reduced. A total of 54 intersection targets were selected by network pharmacology, and Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis showed that UA might regulate ferroptosis in ADMSCs through the PI3K/AKT signaling pathway. Molecular docking showed that UA could stably bind to key proteins. The results of WB showed that UA intervention significantly increased the expression levels of glutathione peroxidase 4 (GPX4), phospho-protein kinase B (p-AKT) and phospho-phosphoinositide 3-kinase (p-PI3K) in ADMSCs damaged by high glucose and high palmitic acid but decreased the expression level of long-chain acyl-CoA synthetase 4 (ACSL4). Conclusion: UA can reverse ferroptosis induced by high glucose and high palmitic acid in ADMSCs, and the mechanism may be related to the regulation of the downstream GPX4/ACSL4 signaling pathway of ferroptosis by activating the PI3K/AKT signaling pathway.

Key words: urolithin A; high glucose and high palmitic acid; adipose-derived mesenchymal stem cells; ferroptosis; phosphoinositide 3-kinase/protein kinase B

中图分类号:

R965

周克春，李包娟，王若彤，张䶮之. 尿石素A激活PI3K/AKT通路抑制高糖高脂介导的脂肪间充质干细胞铁死亡[J]. 食品科学, 2025, 46(21): 180-189.

ZHOU Kechun, LI Baojuan, WANG Ruotong, ZHANG Yanzhi. Urolithin A Inhibits Ferroptosis Induced by High Glucose and Palmitic Acid in Adipose-Derived Mesenchymal Stem Cells by Activating the PI3K/AKT Pathway[J]. FOOD SCIENCE, 2025, 46(21): 180-189.

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尿石素A激活PI3K/AKT通路抑制高糖高脂介导的脂肪间充质干细胞铁死亡

Urolithin A Inhibits Ferroptosis Induced by High Glucose and Palmitic Acid in Adipose-Derived Mesenchymal Stem Cells by Activating the PI3K/AKT Pathway

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