黑龙江中医药大学基础医学院/黑龙江省中医基础理论研究重点实验室,哈尔滨 150040
Received:27 March 2025,
Revised:2025-06-11,
Accepted:18 July 2025,
Published:28 November 2025
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闫丽爽,张健,吴伟东等.中药调控HIF-1α信号通路治疗缺血性脑卒中的研究进展[J].重庆医科大学学报,2025,50(11):1457-1464.
Yan Lishuang,Zhang Jian,Wu Weidong,et al.Research advances in traditional Chinese medicine for treating ischemic stroke by regulating the hypoxia-inducible factor 1α signaling pathway[J].Journal of Chongqing Medical University,2025,50(11):1457-1464.
闫丽爽,张健,吴伟东等.中药调控HIF-1α信号通路治疗缺血性脑卒中的研究进展[J].重庆医科大学学报,2025,50(11):1457-1464. DOI: 10.13406/j.cnki.cyxb.003909.
Yan Lishuang,Zhang Jian,Wu Weidong,et al.Research advances in traditional Chinese medicine for treating ischemic stroke by regulating the hypoxia-inducible factor 1α signaling pathway[J].Journal of Chongqing Medical University,2025,50(11):1457-1464. DOI: 10.13406/j.cnki.cyxb.003909.
缺血性脑卒中(ischemic stroke,IS)是由于脑血管血液和氧气供应不足引起的疾病,临床表现为偏瘫、感觉障碍、失语和共济失调等症状。研究发现,缺氧诱导因子-1α(hypoxia-inducible factor-1α,HIF-1α)作为氧稳态的核心调控元件,在缺氧/缺血条件下可被快速激活,在缺血性脑卒中的病理生理学中发挥广泛作用。近年来越来越多的文章表明中药活性成分、中成药及复方可有效调控HIF-1α相关信号通路治疗缺血性脑卒中,但目前缺少关于中药调控HIF-1α信号通路治疗缺血性脑卒中相关系统总结,故本文主要概述了HIF-1α的结构及生理活性及其在IS中的相关机制,回顾国内外近5年来单体和复方调控HIF-1α通路促进血管新生、抑制神经炎症和氧化应激、促进能量代谢、修复血脑屏障损伤方面修护脑组织、减轻脑组织损伤、进而治疗IS,以期为今后中药临床治疗IS提供研究思路和科学基础。
Ischemic stroke(IS) is a disease caused by insufficient blood and oxygen supply to cerebral vessels,with the main clinical manifestations of hemiplegia,sensory disturbance,aphasia,and ataxia. Studies have shown that hypoxia-inducible factor 1α (HIF-1α),as the core regulatory element of oxygen homeostasis,can be rapidly activated under hypoxia/ischemia conditions,thereby playing an important role in the pathophysiology of IS. In recent years,more and more articles have shown that the active components of traditional Chinese medicine,Chinese patent drugs,and compound traditional Chinese medicine prescriptions can effectively regulate the HIF-1α-related signaling pathway in the treatment of IS,but there is no systematic summary on regulation of the HIF-1α signaling pathway in the treatment of IS. Therefore,this article mainly summarizes the structure and physiological activity of HIF-1α and its mechanisms of action in IS and reviews related studies on Chinese medicine monomers and compound prescriptions in the treatment of IS in the past five years in China and globally. It is pointed out that the Chinese medicine monomers and compound prescriptions can repair brain tissue,alleviate brain tissue damage,and exert a therapeutic effect on IS by regulating the HIF-1α pathway to promote angiogenesis,inhibit neuroinflammation and oxidative stress,promote energy metabolism,and repair blood-brain barrier damage.
Hilkens NA , Casolla B , Leung TW , et al . Stroke [J ] . Lancet , 2024 , 403 ( 10446 ): 2820 - 2836 .
丁元庆 . 中风多元性与中风病机链相关问题探讨 [J ] . 山东中医药大学学报 , 2021 , 45 ( 4 ): 423 - 428 .
Ding YQ . Discussion on issues related to diversity and pathogenesis chain of stroke [J ] . J Shandong Univ Tradit Chin Med , 2021 , 45 ( 4 ): 423 - 428 .
Amin N , Abbasi IN , Wu F , et al . The Janus face of HIF-1α in ischemic stroke and the possible associated pathways [J ] . Neurochem Int , 2024 , 177 : 105747 .
Fong GH , Takeda K . Role and regulation of prolyl hydroxylase domain proteins [J ] . Cell Death Differ , 2008 , 15 ( 4 ): 635 - 641 .
Yu F , White SB , Zhao Q , et al . HIF-1alpha binding to VHL is regulated by stimulus-sensitive proline hydroxylation [J ] . Proc Natl Acad Sci USA , 2001 , 98 ( 17 ): 9630 - 9635 .
Lee JW , Bae SH , Jeong JW , et al . Hypoxia-inducible factor (HIF-1)alpha: its protein stability and biological functions [J ] . Exp Mol Med , 2004 , 36 ( 1 ): 1 - 12 .
Fang J , Wang Z , Miao CY . Angiogenesis after ischemic stroke [J ] . Acta Pharmacol Sin , 2023 , 44 ( 7 ): 1305 - 1321 .
Sun YJ , Jin KL , Xie L , et al . VEGF-induced neuroprotection,neurogenesis,and angiogenesis after focal cerebral ischemia [J ] . J Clin Invest , 2003 , 111 ( 12 ): 1843 - 1851 .
Ren CH , Yao Y , Han RR , et al . Cerebral ischemia induces angiogenesis in the peri-infarct regions via Notch1 signaling activation [J ] . Exp Neurol , 2018 , 304 : 30 - 40 .
Yang J , Liu CY , Du XN , et al . Hypoxia inducible factor 1α plays a key role in remote ischemic preconditioning against stroke by modulating inflammatory responses in rats [J ] . J Am Heart Assoc , 2018 , 7 ( 5 ): e007589 .
Althaus J , Bernaudin M , Petit E , et al . Expression of the gene encoding the pro-apoptotic BNIP3 protein and stimulation of hypoxia-inducible factor-1alpha(HIF-1alpha) protein following focal cerebral ischemia in rats [J ] . Neurochem Int , 2006 , 48 ( 8 ): 687 - 695 .
Ajoolabady A , Wang SY , Kroemer G , et al . Targeting autophagy in ischemic stroke: From molecular mechanisms to clinical therapeutics [J ] . Pharmacol Ther , 2021 , 225 : 107848 .
Nakatogawa H . Mechanisms governing autophagosome biogenesis [J ] . Nat Rev Mol Cell Biol , 2020 , 21 ( 8 ): 439 - 458 .
Liu Z , Tang YH , Zhang ZJ , et al . Engineering neurovascular unit and blood-brain barrier for ischemic stroke modeling [J ] . Adv Healthc Mater , 2023 , 12 ( 19 ): e2202638 .
Abdullahi W , Tripathi D , Ronaldson PT . Blood-brain barrier dysfunction in ischemic stroke:targeting tight junctions and transporters for vascular protection [J ] . Am J Physiol Cell Physiol , 2018 , 315 ( 3 ): C343 - C356 .
Nguyen AQ , Cherry BH , Scott GF , et al . Erythropoietin:powerful protection of ischemic and post-ischemic brain [J ] . Exp Biol Med(Maywood) , 2014 , 239 ( 11 ): 1461 - 1475 .
Zeng ML , Shao CY , Zhou HF , et al . Protocatechudehyde improves mitochondrial energy metabolism through the HIF1α/PDK1 signaling pathway to mitigate ischemic stroke-elicited internal capsule injury [J ] . J Ethnopharmacol , 2021 , 277 : 114232 .
Madai S , Kilic P , Schmidt RM , et al . Activation of the hypoxia-inducible factor pathway protects against acute ischemic stroke by reprogramming central carbon metabolism [J ] . Theranostics , 2024 , 14 ( 7 ): 2856 - 2880 .
Wu XG , Wang CL , Wang JB , et al . Hypoxia preconditioning protects neuronal cells against traumatic brain injury through stimulation of glucose transport mediated by HIF-1α/GLUTs signaling pathway in rat [J ] . Neurosurg Rev , 2021 , 44 ( 1 ): 411 - 422 .
Zhang YL , Liu Y , Cui Q , et al . Hydroxysafflor yellow a alleviates ischemic stroke in rats via HIF-1 [formula:see text ] ,BNIP3,and Notch1-mediated inhibition of autophagy [J ] . Am J Chin Med , 2022 , 50 ( 3 ): 799 - 815 .
姚芬芬 , 张 芳 , 阮玲 , 等 . 羟基红花黄色素A对老年局灶性大脑中动脉脑缺血大鼠神经元自噬的作用及其机制 [J ] . 中国老年学杂志 , 2024 , 44 ( 18 ): 4498 - 4503 .
Yao FF , Zhang F , Ruan L , et al . Effect and mechanism of hydroxysafflor yellow A on autophagy of neurons in aged rats with focal middle cerebral artery ischemia [J ] . Chin J Gerontol , 2024 , 44 ( 18 ): 4498 - 4503 .
Ruan JX , Wang L , Dai JH , et al . Hydroxysafflor yellow a promotes angiogenesis in rat brain microvascular endothelial cells injured by oxygen-glucose deprivation/reoxygenation(OGD/R) through SIRT1-HIF-1α-VEGFA signaling pathway [J ] . Curr Neurovasc Res , 2021 , 18 ( 4 ): 415 - 426 .
Li Y , Liu XT , Zhang PL , et al . Hydroxysafflor yellow a blocks HIF-1 α induction of NOX2 and protects ZO-1 protein in cerebral microvascular endothelium [J ] . Antioxidants(Basel) , 2022 , 11 ( 4 ): 728 .
Wang CH , Wang ZH , Zhang XJ , et al . Protection by silibinin against experimental ischemic stroke:up-regulated pAkt,pmTOR,HIF-1α and Bcl-2,down-regulated Bax,NF-κB expression [J ] . Neurosci Lett , 2012 , 529 ( 1 ): 45 - 50 .
陈 笛 , 温昌明 , 周 静 , 等 . 二氢杨梅素调节HIF-1α/BNIP3信号通路对脑卒中大鼠神经元自噬和凋亡的影响 [J ] . 中国老年学杂志 , 2024 , 44 ( 13 ): 3249 - 3253 .
Chen D , Wen CM , Zhou J , et al . Effects of dihydromyricetin on autophagy and apoptosis of neurons in stroke rats by regulating HIF-1α/BNIP3 signaling pathway [J ] . Chin J Gerontol , 2024 , 44 ( 13 ): 3249 - 3253 .
He QS , Li SR , Li LL , et al . Total flavonoids in Caragana (TFC) promotes angiogenesis and enhances cerebral perfusion in a rat model of ischemic stroke [J ] . Front Neurosci , 2018 , 12 : 635 .
王 敏 , 卢怀海 , 庞旭阳 , 等 . 川陈皮素对脑梗死缺血再灌注大鼠的保护作用及其机制研究 [J ] . 现代生物医学进展 , 2022 , 22 ( 14 ): 2642 - 2647 .
Wang M , Lu HH , Pang XY , et al . Protective effect of tangerine on rats with cerebral infarction and its mechanism [J ] . Prog Mod Biomed , 2022 , 22 ( 14 ): 2642 - 2647 .
杨静帆 , 李敏艳 , 秦燕勤 , 等 . 川陈皮素的药理活性研究进展 [J ] . 中医学报 , 2023 , 38 ( 4 ): 719 - 725 .
Yang JF , Li MY , Qin YQ , et al . Research progress on pharmacological activity of nobiletin [J ] . Acta Chin Med , 2023 , 38 ( 4 ): 719 - 725 .
张小良 , 高赛红 , 杨迎春 , 等 . 白藜芦醇通过上调HIF-1α/BNIP3通路诱导自噬而减轻大鼠脑缺血再灌注损伤 [J ] . 中国病理生理杂志 , 2024 , 40 ( 7 ): 1253 - 1260 .
Zhang XL , Gao SH , Yang YC , et al . Resveratrol alleviates cerebral ischemia-reperfusion injury in rats by activating autophagy via up-regulation of HIF-1α/BNIP3 pathway [J ] . Chin J Pathophysiol , 2024 , 40 ( 7 ): 1253 - 1260 .
Li MC , Jia JT , Wang YX , et al . Astragaloside IV promotes cerebral tissue restoration through activating AMPK- mediated microglia polarization in ischemic stroke rats [J ] . J Ethnopharmacol , 2024 , 334 : 118532 .
Xiao HY , Liu SS , Fang BY , et al . Panax notoginseng saponins promotes angiogenesis after cerebral ischemia-reperfusion injury [J ] . J Ginseng Res , 2024 , 48 ( 6 ): 592 - 602 .
Gao JL , Yao MJ , Zhang W , et al . Panax notoginseng saponins alleviates inflammation induced by microglial activation and protects against ischemic brain injury via inhibiting HIF-1α/PKM2/STAT3 signaling [J ] . Biomed Pharmacother , 2022 , 155 : 113479 .
周静怡 , 刘 秋 , 杨昊 , 等 . 银杏内酯K调节缺氧诱导因子-1α通路抑制氧糖剥离再灌注诱导的神经血管单元损伤 [J ] . 中国药理学通报 , 2021 , 37 ( 5 ): 645 - 652 .
Zhou JY , Liu Q , Yang H , et al . Ginkgolide K inhibited neurovascular unit injury against oxygen-glucose deprivation and reperfusion by regulating hypoxia-inducible factor-1α pathway [J ] . Chin Pharmacol Bull , 2021 , 37 ( 5 ): 645 - 652 .
王哲义 . 丹参酮ⅡA磺酸钠调控HIF1α/mTOR介导细胞自噬干预缺血性脑卒中的机制研究 [D ] . 北京 : 北京中医药大学 , 2021 .
Wang ZY . Effect of tanshinone Ⅱ a sulfonate on HIF1 α/mTOR mediated autophagy in ischemic stroke [D ] . Beijing : Beijing University of Chinese Medicine , 2021 .
Chen XJ , Qian WQ , Zhang Y , et al . Ginsenoside CK cooperates with bone mesenchymal stem cells to enhance angiogenesis post-stroke via GLUT1 and HIF-1α/VEGF pathway [J ] . Phytother Res , 2024 , 38 ( 8 ): 4321 - 4335 .
吕保江 . 基于HIF-1α/VEGFA通路的大黄素对MCAO大鼠机制研究 [D ] . 广州 : 广州中医药大学 , 2022 .
Lü BJ . Mechanism of emodin on MCAO rats based on HIF-1α/VEGFA pathway [D ] . Guangzhou : Guangzhou University of Chinese Medicine , 2022 .
Chen ZZ , Gong X , Guo Q , et al . Bu Yang Huan Wu decoction prevents reperfusion injury following ischemic stroke in rats via inhibition of HIF-1 α,VEGF and promotion β-ENaC expression [J ] . J Ethnopharmacol , 2019 , 228 : 70 - 81 .
Li PP , He L , Zhang LM , et al . Naoluo Xintong decoction ameliorates cerebral ischemia-reperfusion injury by promoting angiogenesis through activating the HIF-1 α /VEGF signaling pathway in rats [J ] . Evid Based Complement Alternat Med , 2022 , 2022 : 9341466 .
乐金海 , 林湘东 , 向 茗 , 等 . 脑泰通组方对局灶性脑缺血再灌注大鼠模型的影响及保护机制 [J ] . 世界中医药 , 2023 , 18 ( 15 ): 2142 - 2147,2153 .
Le JH , Lin XD , Xiang M , et al . Protective effect and mechanism of Naotaitong formula in the rat model of focal cerebral ischemia-reperfusion injury [J ] . World Chin Med , 2023 , 18 ( 15 ): 2142 - 2147,2153 .
王 磊 . 丹灯通脑软胶囊促进脑缺血再灌注损伤大鼠血管新生的保护作用及机制研究 [D ] . 合肥 : 安徽中医药大学 , 2023 .
Wang L . Protective effect and mechanism of Dandeng Tongnao soft capsule on angiogenesis in rats with cerebral ischemia-reperfusion injury [D ] . Hefei : Anhui University of Chinese Medicine , 2023 .
Yang WN , Zhang LC , Chen SM , et al . Longshengzhi capsules improve ischemic stroke outcomes and reperfusion injury via the promotion of anti-inflammatory and neuroprotective effects in MCAO/R rats [J ] . Evid Based Complement Alternat Med , 2020 , 2020 : 9654175 .
Yang T , Liu XL , Zhou Y , et al . Sanpian decoction ameliorates cerebral ischemia-reperfusion injury by regulating SIRT1/ERK/HIF-1α pathway through in silico analysis and experimental validation [J ] . J Ethnopharmacol , 2024 , 318 ( Pt A ): 116898 .
Zhang YQ , Cao YJ , Li Y , et al . Gualou Guizhi decoction promotes therapeutic angiogenesis via th e miR210/HIF/VEGF pathway in vivo and in vitro [J ] . Pharm Biol , 2023 , 61 ( 1 ): 779 - 789 .
张玉琴 , 李亚男 , 冯 怡 , 等 . 栝楼桂枝颗粒通过HIF-1α-Netrin-1-UNC5B/VEGF促进大鼠脑缺血后血管生成和神经功能恢复的研究 [J ] . 中药药理与临床 , 2024 , 40 ( 7 ): 16 - 20 .
Zhang YQ , Li YN , Feng Y , et al . Gualou Guizhi Granule promotes angiogenesis and neurological recovery by improving the expression of HIF-1α-NETRIN-1-UNC5B/VEGF cascade after cerebral ischemic injury in rats [J ] . Pharmacol Clin Chin Mater Med , 2024 , 40 ( 7 ): 16 - 20 .
Zhang QC , Bian HM , Li Y , et al . Preconditioning with the traditional Chinese medicine Huang-Lian-Jie-Du-Tang initiates HIF-1α-dependent neuroprotection against cerebral ischemia in rats [J ] . J Ethnopharmacol , 2014 , 154 ( 2 ): 443 - 452 .
Xiang YY , Yao XQ , Wang X , et al . Houshiheisan promotes angiogenesis via HIF-1α/VEGF and SDF-1/CXCR4 pathways: in vivo and in vitro [J ] . Biosci Rep , 2019 , 39 ( 10 ): BSR20191006 .
Yang FJ , Gu Y , Yan Y , et al . The association of HIF1A gene polymorphism and its expression with ischemic stroke [J ] . Sci Rep , 2025 , 15 ( 1 ): 14600 .
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