醛糖还原酶抑制缺血性脑卒中小胶质内质网应激和铁蛋白吞噬，这一成果由南方医科大学汪海涛团队经过不懈努力而取得。2026年4月27日，国际知名学术期刊《中国药理学报》发表了这一成果。

课题组发现小胶质神经炎症对氧葡萄糖剥夺/再灌注（OGD/R）的反应被山梨醇介导的AR抑制或AR敲低减弱。Sorbinil（5-20μM）可减弱OGD/R诱导的小胶质细胞内质网（ER）应激和下游c-Jun N-末端激酶（JNK）的激活。进一步分析发现，山梨醇抑制小胶质细胞自噬过度激活，降低核受体共激活因子4的表达，升高铁蛋白重链（FTH1）水平。这种效应伴随着FTH1与溶酶体共定位的减少和细胞内铁（Fe²⁺）浓度的降低。重要的是，FTH1敲低可减弱山梨醇对小胶质细胞中Fe²⁺和白细胞介素-1β的抑制作用。

此外，山梨醇还能减轻OGD/R引发的小胶质细胞氧化应激。

此外，山梨醇对暴露于素诱导内质网应激的小胶质细胞也有类似的作用。值得注意的是，山梨醇的保护作用因JNK的药理激活而减弱。在单主题大脑中动脉闭塞/再灌注（MCAO/R）模型中，山梨醇（4、8和16 mg/kg；i.p.）改善MCAO/R模型小鼠的神经功能缺损，减少脑梗死体积。这种抑制与MCAO/R模型小鼠的神经炎症减轻、内质网应激和铁蛋白吞噬的激活相一致。总之，本研究揭示了AR抑制在脑缺血时调节小胶质内质网应激-铁蛋白吞噬信号传导中的新作用。AR是缓解脑缺血再灌注损伤的有前景的治疗靶点。

据悉，醛糖还原酶（AR）参与缺血性卒中的发病机制；然而，其机制尚不清楚。本研究旨在评估AR抑制在缺血性脑卒中中的作用和潜在机制。

附：英文原文

Title: Aldose reductase inhibition suppresses microglial endoplasmic reticulum stress and ferritinophagy in ischemic stroke

Author: Tu, Xing-xing, Luo, Fu-lan, Deng, Ting-wei, Li, Jia-hui, Wang, Jia-kang, Xu, Jiang-ping, Wang, Hai-tao

Issue&Volume: 2026-04-27

Abstract: Aldose reductase (AR) is involved in the pathogenesis of ischemic stroke; however, the mechanisms are not well understood. This study aimed to evaluate the role and underlying mechanisms of AR inhibition in ischemic stroke. We found that microglial neuroinflammatory responses to oxygen glucose deprivation/reperfusion (OGD/R) were attenuated by either sorbinil-mediated AR inhibition or AR knockdown. Sorbinil (5–20μM) attenuated OGD/R-induced endoplasmic reticulum (ER) stress and downstream c-Jun N-terminal kinase (JNK) activation in microglia. Further analysis revealed that sorbinil suppressed microglial autophagic hyperactivation, reduced nuclear receptor coactivator 4 expression, and elevated ferritin heavy chain (FTH1) levels. This effect was accompanied by diminished FTH1 colocalization with lysosomes and decreased intracellular iron (Fe2+) concentrations. Critically, FTH1 knockdown attenuated the inhibitory effect of sorbinil on Fe2+ and interlenkin-1β in microglia. Furthermore, sorbinil mitigated OGD/R-triggered oxidative stress in microglia. Moreover, sorbinil had similar effects on microglia exposed to thapsigargin-induced ER stress. Notably, the protective efficacy of sorbinil was attenuated by the pharmacological activation of JNK. In a mouse middle cerebral artery occlusion/reperfusion (MCAO/R) model, sorbinil (4, 8, and 16mg/kg; i.p.) ameliorated neurological deficits and decreased the volume of cerebral infraction in MCAO/R model mice. This suppression coincided with attenuated neuroinflammation and the activation of ER stress and ferritinophagy in MCAO/R model mice. Overall, this study reveals a novel role of AR inhibition in regulating microglial ER stress–ferritinophagy signaling during cerebral ischemia. AR represents a promising therapeutic target for mitigating cerebral ischemiareperfusion injury.

DOI: 10.1038/s41401-026-01796-8

Source: https://www.nature.com/articles/s41401-026-01796-8