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虫草素通过Nrf2/HO-1通路抑制铁死亡延缓AKI向CKD转化的作用机制研究
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| 篇名： | 虫草素通过Nrf2/HO-1通路抑制铁死亡延缓AKI向CKD转化的作用机制研究 |
| TITLE： | Study on the mechanism of cordycepin inhibiting ferroptosis via the Nrf2/HO-1 pathway to delay the transformation from AKI to CKD |
| 摘要： | 目的 研究虫草素延缓急性肾损伤（AKI）向慢性肾脏病（CKD）（以下简称“AKI-CKD”）转化的作用机制。方法采用网络药理学和生物信息学分析并预测虫草素延缓AKI-CKD的信号通路及其与铁死亡途径的关系。采用细胞实验对预测结果进行验证：将人肾小管上皮细胞HK-2分为空白组、虫草素组、模型组、H2O2+虫草素组，除空白组和虫草素组外，其余各组加入150μmol/LH2O2处理72h以诱导细胞持续性氧化应激损伤；虫草素（40μmol/L）干预72h后，检测细胞中谷胱甘肽过氧化物酶4（GPX4）、长链脂酰辅酶A合成酶4（ACSL4）、核转录因子红系2相关因子2（Nrf2）、血红素加氧酶1（HO-1）蛋白和mRNA表达水平。另在H2O2+虫草素的基础上引入Nrf2抑制剂ML385以验证Nrf2/HO-1通路的作用。结果网络药理学及生物信息学分析结果显示，虫草素与AKI-CKD及铁死亡相关的交集基因有42个，其中38个被注释为铁死亡相关基因；HO-1与Nrf2可能是虫草素抑制铁死亡的重要靶点，虫草素与Nrf2、HO-1蛋白的结合能分别为－8.5、－6.7kcal/mol。细胞实验结果显示，与模型组比较，H2O2+虫草素组细胞中GPX4、Nrf2、HO-1蛋白和mRNA表达水平均显著升高（P＜0.05），ACSL4蛋白和mRNA表达水平均显著降低（P＜0.05）；加入Nrf2抑制剂ML385后，虫草素对上述蛋白和mRNA的作用被显著逆转（P＜0.05）。结论虫草素可通过激活Nrf2/HO-1通路抑制铁死亡，减轻肾小管上皮细胞持续性氧化应激损伤，延缓AKI-CKD进展。 |
| ABSTRACT： | OBJECTIVE To investigate the mechanism of cordycepin in delaying the transformation from acute kidney injury （AKI） to chronic kidney disease （CKD） （short for “AKI-CKD”）. METHODS Network pharmacology and bioinformatics were used to analyze and predict the signaling pathways of cordycepin in delaying AKI-CKD progression and its relationship with the ferroptosis pathway. Cell experiments were performed to verify the predicted results. Human renal tubular epithelial HK-2 cells were divided into blank group， cordycepin group， model group， and H 2 O 2 +cordycepin group. Except for the blank group and cordycepin group， all other groups were treated with 150 μmol/L H 2 O 2 for 72 h to induce persistent oxidative stress injury in cells. After 72 h of cordycepin （40 μmol/L） intervention， the protein and mRNA expression levels of glutathione peroxidase 4 （GPX4）， long-chain acyl-CoA synthetase 4 （ACSL4），nuclear factor-erythroid 2-related factor 2（Nrf2）， and heme oxygenase-1 （HO-1） in cells were detected. Furthermore， the Nrf2 inhibitor ML385 was added on the basis of H 2 O 2 +cordycepin to verify the role of the Nrf2/HO-1 pathway. RESULTS Network pharmacology and bioinformatics analysis showed that there were 42 overlapping genes related to AKI-CKD and ferroptosis that interact with cordycepin ferroptosis， among which 38 were annotated as ferroptosis-related genes. HO-1 and Nrf2 might be important targets for cordycepin to inhibit ferroptosis. The binding energies of cordycepin with Nrf2 and HO-1 proteins were －8.5 and －6.7 kcal/mol， respectively. Cell experiments showed that compared with the model group， the protein and mRNA expression levels of GPX4， Nrf2 and HO-1 were significantly increased （ P ＜0.05），while the protein and mRNA expression levels of ACSL4 were significantly decrease d （ P ＜0.05） in the H 2 O 2 +cordycepin group. After the addition of the Nrf2 inhibitor ML385， the effects of cordycepin on the above proteins and mRNA were significantly reversed （ P ＜0.05）. CONCLUSIONS Cordycepin can inhibit ferroptosis by activating the Nrf2/HO-1 pathway， reduce persistent oxidative stress injury of renal tubular epithelial cells， and delay the progression of AKI-CKD. |
| 期刊： | 2026年第37卷第11期 |
| 作者： | 白梦琦；李俊虎；赵志波；周晓霜 |
| AUTHORS： | BAI Mengqi，LI Junhu，ZHAO Zhibo，ZHOU Xiaoshuang |
| 关键字： | 虫草素; 急性肾损伤; 慢性肾脏病; Nrf2/HO-1通路; 铁死亡; 网络药理学; 生物信息学 |
| KEYWORDS： | cordycepin; acute kidney injury; chronic kidney disease; Nrf2/HO-1 pathway; ferroptosis; network pharmacology; bioinformatics |
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