[1]贾小慧,王泽宇,田嘉莹,等.丹参酮ⅡA通过抑制细胞色素P450 1B1/长链酰基辅酶A合成酶4通路介导铁死亡缓解缺血性脑卒中[J].陕西医学杂志,2025,54(7):882-887,913.[doi:DOI:10.3969/j.issn.1000-7377.2025.07.003]
　JIA Xiaohui,WANG Zeyu,TIAN Jiaying,et al.Tanshinone ⅡA alleviates ischemic stroke by suppressing cytochrome P450 1B1/acyl-CoA synthetase long-chain family member 4 (CYP1B1/ACSL4)-mediated ferroptosis[J].,2025,54(7):882-887,913.[doi:DOI:10.3969/j.issn.1000-7377.2025.07.003]
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丹参酮ⅡA通过抑制细胞色素P450 1B1/长链酰基辅酶A合成酶4通路介导铁死亡缓解缺血性脑卒中

《陕西医学杂志》[ISSN:1000-7377/CN:61-1281/TN]

卷:
54
期数:
2025年7期
页码:
882-887,913
栏目:
基础研究
出版日期:
2025-07-05

文章信息/Info

Title:
Tanshinone ⅡA alleviates ischemic stroke by suppressing cytochrome P450 1B1/acyl-CoA synthetase long-chain family member 4 (CYP1B1/ACSL4)-mediated ferroptosis
作者:
贾小慧 ; 王泽宇; 田嘉莹; 戚询中; 盛宝英
（佳木斯大学附属第一医院，黑龙江 佳木斯 154002）
Author(s):
JIA Xiaohui; WANG Zeyu; TIAN Jiaying; QI Xunzhong; SHENG Baoying
（The First Affiliated Hospital of Jiamusi University,Jiamusi 154002，China）
关键词:
细胞色素P450家族1亚基B1; 酰基辅酶A合成酶长链家族成员4; 丹参酮ⅡA; 铁死亡; 缺血性脑卒中
Keywords:
CYP1B1; ACSL4; Tanshinone ⅡA; Ferroptosis; Ischemic stroke
分类号:
R 743
DOI:
DOI:10.3969/j.issn.1000-7377.2025.07.003
文献标志码:
A
摘要:
目的：研究丹参酮ⅡA（Tan ⅡA）对缺血性脑卒中（IS）的影响，并探讨该过程中涉及的潜在机制。方法：实验造模采用大脑中动脉阻塞（MCAO）小鼠模型和HT-22细胞氧糖剥夺/再灌注（OGD/R）模型。MCAO小鼠分别接受5、10 mg/kg丹参酮ⅡA治疗，HT-22细胞在OGD/R处理后给予不同浓度丹参酮ⅡA干预。通过TTC染色评估脑梗死体积，TUNEL染色检测神经元凋亡，DCFH-DA探针测定活性氧（ROS）水平，Western blot分析细胞色素P450家族1亚基B1（CYP1B1）、酰基辅酶A合成酶长链家族成员4（ACSL4）及下游相关蛋白表达。通过过表达或敲低CYP1B1结合泛素化实验探究机制。结果：丹参酮ⅡA显著减少MCAO小鼠脑梗死面积、神经功能缺损及脑水肿。在OGD/R细胞中，丹参酮ⅡA提升细胞活力，降低ROS和ACSL4蛋白表达。此外，丹参酮ⅡA通过上调CYP1B1促进ACSL4泛素化降解，其代谢产物20-羟二十碳四烯酸（20-HETE）激活蛋白激酶C（PKC）信号通路，诱导E3泛素连接酶FBXO10表达，从而增强ACSL4降解。结论：丹参酮ⅡA通过CYP1B1/ ACSL4通路促进ACSL4泛素化降解，抑制铁死亡（Ferroptosis），为缺血性脑卒中治疗提供新靶点。
Abstract:
Objective:To investigate the effect of Tanshinone ⅡA (Tan ⅡA) on ischemic stroke and explore the underlying mechanisms.Methods：Middle cerebral artery occlusion (MCAO) in mice and oxygen-glucose deprivation/reperfusion (OGD/R) in HT-22 cells were used as experimental models.MCAO mice were treated with 5 or 10 mg/kg Tan ⅡA,while HT-22 cells were exposed to different concentrations of Tan ⅡA post-OGD/R.Brain infarction volume was assessed by TTC staining.Neuronal apoptosis was detected by TUNEL assay,and reactive oxygen species (ROS) levels were measured by DCFH-DA probe.Western blotting analyzed the expressions of cytochrome P450 family 1 subfamily B member 1 (CYP1B1),acyl-CoA synthetase long-chain family member 4 (ACSL4),and downstream proteins.Overexpression or knockdown of CYP1B1,combined with ubiquitination assays,was performed to elucidate the mechanism.Results:Tan ⅡA significantly reduced cerebral infarction area,neurological deficits,and brain edema in MCAO mice.In OGD/R-treated HT-22 cells,Tan ⅡA enhanced cell viability,decreased ROS levels,and downregulated ACSL4 expression.Mechanistically,Tan ⅡA promoted the ubiquitination and degradation of ACSL4 by upregulating CYP1B1.The CYP1B1 metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) activated the protein kinase C (PKC) pathway to induce the expression of E3 ubiquitin ligase FBXO10,thereby accelerating ACSL4 degradation.Conclusion:Tan ⅡA inhibits ferroptosis in ischemic stroke by facilitating ACSL4 ubiquitination via the CYP1B1/ACSL4 axis,offering a novel therapeutic target for ischemic stroke.

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备注/Memo

备注/Memo:
黑龙江省自然科学基金资助项目（PL2024H008）;黑龙江省中医药科研项目（ZHY2024-205）
更新日期/Last Update: 2025-07-07