| 引用本文: |
马强, 欧阳心怡, 颜思阳, 刘利娟, 周德生.芒柄花素通过影响ACSL4/LPCAT3/GPX4表达缓解脑缺血再灌注损伤中神经元铁死亡[J].湖南中医药大学学报,2025,45(6):989-999[点击复制] |
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| 芒柄花素通过影响ACSL4/LPCAT3/GPX4表达缓解脑缺血再灌注损伤中神经元铁死亡 |
| 马强,欧阳心怡,颜思阳,刘利娟,周德生 |
| (湖南中医药大学, 湖南 长沙 410208;湖南中医药大学第一附属医院, 湖南 长沙 410007) |
| 摘要: |
| 目的 探讨芒柄花素在脑缺血再灌注损伤（CIRI）中是否通过调控ACSL4/LPCAT3/GPX4信号轴，干预神经元铁死亡，发挥神经保护作用。方法 采用改良线栓法建立大鼠大脑中动脉缺血再灌注（MCAO/R）模型，设立假手术组，模型组，芒柄花素低、中、高剂量组及依达拉奉对照组。采用改良神经功能评分（mNSS）评分评估神经功能，HE、尼氏及镀银染色观察脑组织病理改变，TUNEL染色检测神经元凋亡。同时检测Fe2+、丙二醛（MDA）、脂质过氧化物（LPO）、还原型谷胱甘肽/氧化型谷胱甘肽（GSH/GSSG）及活性氧（ROS）水平以评价铁死亡程度，并采用Western blot、流式细胞术、免疫荧光检测铁死亡关键蛋白ACSL4、LPCAT3、ALOX1和GPX4表达。结果 与模型组相比，芒柄花素显著改善大鼠神经功能缺损和组织病理改变，降低凋亡细胞比例及铁死亡相关指标（Fe2+、MDA、LPO、ROS），并提高抗氧化水平（GSH/GSSG）（P<0.05，P<0.01）。Western blot结果显示，芒柄花素下调ACSL4、LPCAT3、ALOX15蛋白表达，上调GPX4蛋白表达；流式细胞术结果显示，芒柄花素显著降低了ACSL4/LPCAT3双阳性细胞表达比例（P<0.01）；免疫荧光结果显示芒柄花素降低了脑组织中ACSL4和LPCAT3表达水平（P<0.05，P<0.01）。结论 芒柄花素可通过调控ACSL4/LPCAT3/GPX4蛋白表达，抑制铁死亡，缓解CIRI所致神经损伤，为其在缺血性脑卒中辅助治疗中的应用提供理论支持。 |
| 关键词: 脑缺血再灌注损伤 芒柄花素 铁死亡 ACSL4/LPCAT3/GPX4轴 神经保护 |
| DOI：10.3969/j.issn.1674-070X.2025.06.001 |
| 投稿时间：2025-03-30 |
| 基金项目:湖南省自然科学基金面上项目（2024JJ5313）；湖南中医药大学研究生创新课题（2023CX29）。 |
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| Formononetin alleviates neuronal ferroptosis in cerebral ischemia-reperfusion injury by modulating ACSL4/LPCAT3/GPX4 expression |
| MA Qiang, OUYANG Xinyi, YAN Siyang, LIU Lijuan, ZHOU Desheng |
| (Hunan University of Chinese Medicine, Changsha, Hunan 410208, China;The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China) |
| Abstract: |
| Objective To investigate whether formononetin exerts neuroprotective effects in cerebral ischemia-reperfusion injury (CIRI) by regulating the ACSL4/LPCAT3/GPX4 signaling axis to inhibit neuronal ferroptosis.Methods The modified suture method was used to establish a rat model of middle cerebral artery occlusion/reperfusion (MCAO/R). A sham operation group, a model group, low-, medium-, and high-dose formononetin (FMN) groups, and an edaravone control group were set up. Neurological function was assessed using the modified neurological severity score (mNSS). Histopathological changes in brain tissue were evaluated by HE, Nissl, and silver staining. Neuronal apoptosis was detected by TUNEL staining. The levels of Fe2+, MDA, LPO, GSH/GSSG, and ROS were simultaneously measured to assess ferroptosis, while Western blot, flow cytometry, and immunofluorescence were used to detect the expression of key ferroptosis-related proteins.Results Compared with the model group, formononetin significantly improved the neurological deficits and histopathological changes in rats, reduced the proportion of apoptotic cells and ferroptosis-related indicators (Fe2+, MDA, LPO, ROS), and increased antioxidant level (GSH/GSSG) (P<0.05, P<0.01). flow cytometry Results showed that formononetin significantly reduced the expression ratio of ACSL4/LPCAT3 double-positive cells (P<0.01); immunofluorescence Results showed that formononetin reduced the expression levels of ACSL4 and LPCAT3 in brain tissue (P<0.05, P<0.01).Conclusion Formononetin can inhibit ferroptosis by regulating the expression of ACSL4/LPCAT3/GPX4, alleviate nerve injury caused by CIRI, and provide theoretical support for its application in the adjuvant treatment of ischemic stroke. |
| Key words: cerebral ischemia-reperfusion injury formononetin ferroptosis ACSL4/LPCAT3/GPX4 axis neuroprotection |
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