Introduction

Ischemic stroke (IS), also known as cerebral infarction, is an ischemic lesion resulting from the temporary or permanent interruption of local cerebral blood flow. It leads to ischemic and hypoxic necrosis of brain tissue and a rapid onset of neurological impairment.1,2 Patients with IS primarily exhibit symptoms such as decline in limb function, language and motor disorders, and severe neurological deficits, including hemiplegia. The number of deaths worldwide due to IS increased from 2.04 million in 1990 to 3.29 million in 2019, with projections suggesting a rise to 4.9 million by 2030.3 Furthermore, approximately 540,000 people suffer from stroke each year, with about three-quarters of survivors experiencing varying degrees of disability, and the severe disability rate reaches as high as 40%.4 IS is the second leading cause of death globally, imposing a substantial burden on healthcare systems and economies.

The pathogenesis of IS primarily involves arterial occlusion and arterial embolism, encompassing various pathological factors such as excitotoxicity of amino acids, calcium ion overload, oxidative stress, inflammation, and apoptosis.5–8 The core of IS treatment lies in achieving vascular recanalization and restoring cerebral tissue reperfusion. However, It often results in cerebral ischemia-reperfusion injury (CIRI). Even with timely reperfusion, patients may still experience severe neurological deficits.3 In clinical practice, thrombolytic therapy serves as the cornerstone strategy for IS. Tissue plasminogen activator (tPA) is the only FDA-approved drug for promoting vascular reconstruction and neurological recovery in IS. However, its clinical use is limited by a narrow therapeutic window and risks of hemorrhage, secondary injury, and neurotoxicity.9,10 Alternative neuroprotective strategies, such as calcium channel and glutamate antagonists, have shown limited success in clinical trials due to their reliance on animal-based targets. Consequently, there is a pressing need for new, broadly applicable treatments for IS.

Buyang Huanwu Decoction (BYHWD), originating from Yilin Gaicuo, is a widely used traditional Chinese medicine (TCM) for treating stroke and its sequelae, particularly in East Asia.11–13 Recent pharmacological studies have revealed its neuroprotective effects, including promoting nerve cell growth, inhibiting apoptosis and inflammation, improving cerebral microcirculation, and reducing free radical concentration.14,15 In terms of the therapeutic time window, Animal experiments have shown that BYHWD has shown significant potential in treating CIRI when administered within four hours after stroke.16 Furthermore, BYHWD has demonstrated superior clinical efficacy compared to rt-PA, Xuefu Zhuyu Decoction, and Tianma Gouteng Decoction in improving brain function, reducing infarction, and alleviating neurological deficits.17

Previous reviews generally focus on the clinical efficacy of BYHWD or isolated neuroprotective mechanisms, lacking a comprehensive analysis of its multi-component, multi-pathway, and holistic therapeutic effects, and rarely explore the application of its derivatives or integration with modern medicine. This review fills this gap by detailing the key signaling pathways and therapeutic targets involved in treatment of IS with BYHWD, including the Phosphoinositide 3-kinase (PI3K) -Akt pathway, autophagy, Nuclear factor erythroid-2-related factor 2 (Nrf2), vascular endothelial growth factor (VEGF), inflammasome, the Notch, NF-κB, and ferroptosis, as illustrated in Figure 1. Additionally, it explores how BYHWD promotes neurological recovery through synaptic plasticity regulation and offers insights into its long-term brain repair potential. The review also covers the clinical progress of BYHWD and its derivatives, offering a robust foundation for future development and integration of TCM-based treatments for IS. It is anticipated that this review will provide a robust theoretical foundation for further in-depth research and development of BYHWD, guide the development of anti-IS drugs based on the holistic treatment philosophy of TCM formulations, and promote the innovative application of traditional prescriptions in modern medicine.

Figure 1 BYHWD improves IS by mediating the PI3K-Akt pathway, autophagy, Nrf2, and related pathways.

Abbreviations: BYHWD, Buyang Huanwu Decoction; IS, Ischemic stroke; VEGFR2, vascular endothelial growth factor receptor 2; PI3K, Phosphoinositide 3-kinase; S1P, sphingosine 1-phosphate; S1PR1, S1P receptor; GSK-3, glycogen synthase kinase 3; SirT1, Sirtuin 1; BDNF, brain-derived neurotrophic factor; DCX, doublecortin; PKCε, Protein Kinase C epsilon; Nrf2, Nuclear factor erythroid-2-related factor 2; HO-1, heme oxygenase-1; Nampt, nicotinamide phosphoribosyl transferase; GSH-PX, glutathione peroxidase.

The Therapeutic Effects of BYHWD on IS

BYHWD, a classic prescription for treating stroke, is composed of Huangqi, Dangguiwei, Chishao, Dilong, Chuanxiong, Honghua, and Taoren.4 We summarize the primary pharmacological effects, targets, and pathways of these herbs in the treatment of IS, aiming to elucidate the mechanistic basis of the synergistic actions of this formula. Furthermore, we present an overview of the principal components of BYHWD and their pharmacological activities. This aims to provide a robust theoretical foundation for further exploration, optimization of clinical applications, and innovative drug development.

Astragalus

A. membranaceus (Huangqi), recognized as the Sovereign Herb in BYHWD, plays a pivotal role in comprehensive treatment of IS, particularly by modulating immune responses and promoting endogenous neural repair. It alleviates CIRI by inhibiting oxidative stress, neuroinflammation, and calcium overload, while improving cognitive function, reducing neurological deficits, and enhancing survival during both acute and chronic recovery phases.18,19 Clinical evidence further indicates that adjunctive Huangqi therapy alleviates post stroke fatigue and improves quality of life.20 The pharmacological effects of Huangqi are primarily attributed to its polysaccharides, flavonoids, and saponins.21 Among these, Astragalus saponins (AS) promote the proliferation of neural stem cells (NSCs), thereby providing a cellular basis for post-brain injury repair.19,22 Astragaloside IV has been reported to reduce ischemic brain injury by regulating lipid mediator production and intracellular calcium homeostasis, thereby preserving blood–brain barrier integrity and neuronal structure in middle cerebral artery occlusion (MCAO) models.23,24 In addition, Astragalus polysaccharides promote microglial polarization toward a reparative phenotype, contributing to the resolution of post-ischemic inflammation.25 Regarding combination therapy, the combined administration of A. membranaceus extract and ligustrazine modulates the NR2B-ERK/CREB pathway, further alleviating CIRI.26 Collectively, Astragalus primarily supports IS recovery by shaping a permissive immune and regenerative microenvironment, rather than acting on a single injury pathway. Future studies should emphasize translational validation through standardized preparations and well-designed clinical trials.

Angelica sinensis

A. sinensis (Dang Gui), a key component of BYHWD, exhibits notable neuroprotective potential in ischemic stroke.27,28 Studies show that Dang Gui promotes neuronal survival, neurogenesis, and dendritic growth during the chronic phase of CIRI, supporting long term neural repair.27 The mechanism may involve the activation of the p38 MAPK pathway and downstream p90RSK/p-Bad, thereby improving cognitive and neurological outcomes.29 The pharmacological activity of Dang Gui is primarily attributed to ferulic acid (FA) and ligustilide. Among these, FA reduces cerebral infarction volume and attenuates ischemic neuronal injury in focal cerebral ischemia models.30 Ligustilide promotes mitophagy via the PINK1/Parkin pathway, ameliorating neuronal damage in IS and providing a novel strategy based on mitochondrial quality control for IS.31 Furthermore, A. sinensis exhibits vascular-protective properties, including enhancement of angiogenesis and inhibition of platelet aggregation.32 In summary, A. sinensis contributes to IS therapy mainly through mitochondrial protection and vascular support, highlighting its role in sustaining neuronal energy homeostasis during post-ischemic recovery. Patients are advised to take the medication after meals to minimize gastrointestinal irritation.

Paeoniae Radix Rubra

P. Radix Rubra (PRR), or Chishao, is derived from the roots of P. lactiflora Pall. or P. veitchii Lynch and exhibits anti-inflammatory and neuroprotective. Modern studies indicate that its major active constituents, including terpenoids, flavonoids, and volatile oils, exert anti-inflammatory, and neuroprotective.32 In transient MCAO models, PRR reduce infarct volume, alleviate cerebral edema, and improve neurological function. Mechanistically, PRR regulates multiple forms of programmed cell death, including apoptosis and ferroptosis, while promoting adaptive autophagy, thereby limiting excessive neuronal loss.33,34 Furthermore, network pharmacology analyses indicate that PRR components interact with key targets involved in neural recovery, angiogenesis, and inflammatory regulation.35 PRR is frequently combined with other herbs to enhance its therapeutic efficacy. With F. Carthami, it ameliorates ischemic brain injury through a synergistic mechanism.35 With L. chuanxiong, it significantly inhibits apoptotic signaling related to endoplasmic reticulum stress and mitigates disruption of the blood-brain barrier (BBB).36 Collectively, PRR functions as a cell-protective modulator within BYHWD. Future studies should further clarify the component interactions of PRR through clinical investigations.

Pheretima (Dilong)

Pheretima (PA) refers to the dried bodies of earthworms such as Pheretima asperillum, which are commonly utilized in the treatment of conditions such as stroke hemiplegia and fever.37 Modern studies have identified 509 compounds within PA, including amino acids, lipids, and proteins, with lumbrokinase recognized as the primary active component. In IS, PA exhibits multifaceted neuroprotective and reparative potential.PA significantly improves neurological deficits in mice, reduces infarct volume, activates the Ang1/Tie2/Ang2 pathway to promote angiogenesis.38 Clinically, Pheretima-derived preparations such as Shuxuetong injection (SXI), are widely used for acute IS. Furthermore, SXI has been shown to protect cerebral microvascular endothelial cells following hypoxia/reperfusion by attenuating inflammatory and endothelial stress responses.39 Overall, Pheretima exerts neuroprotective effects primarily by enhancing microcirculation and angiogenesis, supporting vascular reconstruction during post-ischemic recovery.

L. striatum (Rhizoma Chuanxiong)

Chuanxiong Rhizoma (CR) is the dried rhizome of L. chuanxiong Hort., from which over 220 components have been isolated to date, including phthalides, terpenes, alkaloids, and polysaccharides.40 These constituents exhibit a broad spectrum of pharmacological activities. For instance, FA demonstrates neuroprotective effects, significantly reducing cerebral infarction and neurological deficit.30 In IS, CR enhances cerebral microcirculation and inhibits the overactivation of astrocytes and microglia, thereby mitigating neuroinflammatoryresponses.41 Additionally, CR promotes neurogenesis by enhancing the proliferation and differentiation of neural progenitor cells within the hippocampal region, facilitating post-ischemic neural repair.42 Recent studies have also indicated that CR modulates the JAK-STAT3 pathway, influencing the process of ferroptosis, expanding its mechanistic relevance in IS.43 Taken together, CR contributes to stroke recovery mainly through regulation of neurogenesis and glial responses, warranting further clinical validation.

Safflower (Carthamus tinctorius L)

Safflower (C. tinctorius L). is a classic representative of traditional medicinal herbs in Sichuan, primarily comprising flavonoids, alkaloids, and polyacetylenes.44 To date, more than 100 compounds have been isolated and identified from C. tinctorius, among which quinochalcone C-glycoside hydroxysafflor yellow A (HSYA), N-(p-Coumaroyl)serotonin, and N-feruloylserotonin are the primary contributors to its pharmacological activities.45 Safflower exhibits neuroprotective effects in CIRI by inhibiting platelet aggregation, and reducing cell apoptosis. Its regulation of matrix metalloproteinases (MMPs) helps mitigate BBB disruption and cerebral edema.46,47 HSYA, a key component, reduces brain damage and improves neurological function by inhibiting inflammasome activation (NLRP3, AIM2, Pyrin) during I/R injury.48 Furthermore, flavonoid glycosides such as Kaempferol-3-O-rutinosideand Kaempferol-3-O-glucoside also support anti-inflammatory regulation during ischemic injury.49 In summary, Safflower acts mainly by vascular and BBB protection and controlling inflammatory amplification, playing a complementary role within BYHWD.

Peach Kernel

Peach Kernel (PK), the dried seed of Prunus persica (L). Batsch or P. davidiana (Carr). Franch., s known for its hemorheological and anti-thrombotic effects.The primary components of PK consist of oils and proteins, which account for 54.5% and 27.5% of its composition, respectively, while the levels of ash and total carbohydrates are relatively low. Furthermore, the liposoluble components of PK make up approximately 50% of its dry weight, potentially providing clinical benefits in TCM.50 PK extract has been shown to effectively inhibit ADP-induced platelet aggregation.51 Additionally, research indicates that Amygdalin, a vital component of PK, is a crucial substance in the Taoren formula. Intraperitoneal injection of Amygdalin significantly reduces cerebral infarction volume in rat models of acute IS and enhances neurological function. Moreover, Amygdalin has been found to decrease the expression of uncleaved caspase-3 while increasing the expression of caspase-9, thereby regulating the intrinsic apoptosis pathway to exert neuroprotective effects.52 However, current research on the underlying mechanisms of PK in IS treatment remains limited. Future studies should investigate the molecular mechanisms and clinical applications of PK-based therapies for IS.

The Main Active Compounds of BYHWD and Their Effects on IS

The treatment of IS with BYHWD is characterized by its synergistic effects across multiple components, targets, and pathways. Network pharmacology revealed key compounds targeting oxidative stress, inflammation, and energy metabolism. Sucrose, Lactiflorin, and Albiflorin were key anti-CI/R agents, while HSYA, Paeoniflorin, and Albiflorin mainly regulated inflammation and metabolism, with Lactiflorin also linked to energy metabolism.53 There have been reports selecting 15 absorbable chemical constituents of BYHWD, including FA, calycosin, formononetin, paeonol, calycosin-7-O-β-D-glucoside, astraisoflavan-7-O-β-D-glucoside, ligustrazine, and propyl gallate and others, for investigation.54 These exhibit immunomodulatory effects, inhibiting T cell proliferation and reducing macrophage apoptosis. Furthermore, they suppress abnormal vascular contraction, alleviating cerebral ischemic injury.54 Studies have found that glycosides such as Astragaloside IV, Paeoniflorin, and Amygdalin are key bioactive compounds in BYHWD for treating cerebral infarction.55 Additionally, network pharmacology has identified 42 compounds and 79 genes that constitute the primary pathways related to IS. 16 key compounds such as baicalein, β-carotene, baicalin, kaempferol, luteolin, quercetin, HSYA, isorhamnetin, bifendate, formononetin, calycosin, astragaloside IV, stigmasterol, sitosterol, Z-ligustilide, and dihydrocapsaicin are noteworthy. The core genes also encompass the Toll-like receptor, mitogen-activated protein kinase, and hypoxia-inducible factor 1 pathways, all of which are implicated in IS.56 Overall, these suggest that BYHWD exerts anti-ischemic effects through multi-component regulation of immune, vascular, and inflammatory pathways. However, most findings rely on network analyses, and further experimental validation is needed to clarify the roles in IS.

The Mechanism of BYHWD in Treating IS Multiple Targets and Pathways PI3K-Akt

The PI3K-Akt pathway is a well-established protective mechanism in IS.57 It serves as a crucial mechanism through which BYHWD exerts its effects against IS. BYHWD influences the sphingolipid regulatory system, including sphingosine, ceramide, and sphingosine 1-phosphate (S1P), ultimately modulating the PI3K/Akt pathway. Specifically, BYHWD significantly upregulates SphK2 while downregulating SphK1 expression, thereby affecting S1P synthesis. Binding of S1P to its receptor (S1PR1) subsequently activates PI3K/Akt signaling, which significantly improves neurological deficits and reduces infarct volume in mice subjected to permanent MCAO.58 Upon activation of the PI3K/Akt pathway, Akt phosphorylates the Bad protein at the Ser-136 site. Phosphorylated Bad (P-Bad) interacts with 14-3-3 proteins, inhibits Bax activation, and suppresses caspase-3 activity, thereby reducing neuronal apoptosis and cerebral infarction volume in transient MCAO models.59 Beyond PI3K/Akt signaling alone, BYHWD exerts neuroprotection through coordinated regulation of calcium-related pathways. It elevates the levels of p-PI3K and p-AKT while upregulating calcium signaling-associated molecules such as ATP2B2, PDE1A, and CaMK4. Furthermore, it reduces levels of TNF-α and CD38, alleviates neuroinflammation, decreases infarct volume, and improves neurological scores in MCAO rats.60 Additionally, BYHWD inhibits the activity of glycogen synthase kinase 3 (GSK-3) by enhancing the expression of Akt, PKC, and CaMKII, thereby attenuating ischemia/reperfusion-induced Tau hyperphosphorylation.61 In summary, BYHWD mediates the PI3K-Akt pathway, regulating various molecular mechanisms such as sphingolipid metabolism, apoptosis, and calcium signaling. This regulation significantly improves neurological deficits in stroke, reduces cerebral infarction volume, suppresses inflammation and neuronal apoptosis, and promotes angiogenesis and recovery of neurological function.

Autophagy

Autophagy, recognized as the primary cellular degradation pathway, is essential for maintaining cellular homeostasis. During the onset of IS, autophagy predominantly occurs in the peri-ischemic regions, and its activation has been shown to promote neuroprotection in stroke.62 Sirtuin 1 (SirT1), an NAD+-dependent class III histone deacetylase, targets multiple transcription factors and participates in various physiological processes.63 BYHWD enhances autophagy by promoting the expression of the critical autophagy regulator SIRT1, which in turn increases the levels of beclin 1 and LC3-II while reducing p62 expression. This process ultimately protects neurons from damage in MCAO-rats, promotes neurogenesis, and elevates the levels of nestin, brain-derived neurotrophic factor (BDNF), and doublecortin (DCX).62 Furthermore, the primary active components in BYHWD, glycosides, activate the PINK1/Parkin mitophagy pathway, thereby inhibiting inflammation and exerting neuroprotective effects against cerebral ischemia reperfusion (CIR).64 Meanwhile, the derivative formulation of BYHWD, Qilong capsule (QLC), has demonstrated significant efficacy in treating SI. One of its mechanisms of action involves promoting autophagy, degrading α-synuclein, and facilitating neuronal growth, thereby repairing neural damage induced by MPTP. It alleviates damage to dopaminergic neurons, reduces the number of apoptotic cells in the brain, and mitigates MPTP-induced motor dysfunction. Research has indicated that QLC’s mechanisms of action include the inhibition of mitochondrial apoptosis and the promotion of autophagy.65 In summary, BYHWD exerts neuroprotective effects through the multi-pathway regulation of autophagy. Collectively, these mechanisms alleviate cerebral ischemia and neurotoxic damage, highlighting the multi-target therapeutic potential of BYHWD.

Nrf2

Nrf2 is a pivotal regulatory factor in the endogenous antioxidant defense system, playing a crucial role in reducing infarct size and mitigating ischemia-reperfusion injury. This makes it a significant target for protecting brain cells in the treatment of IS.66 BYHWD can enhance the activity of Protein Kinase C epsilon (PKCε), a subtype of the PKC family, which is essential for maintaining mitochondrial function and cellular homeostasis. BYHWD activates the Nrf2 pathway, leading to an increased expression of nuclear Nrf2 and heme oxygenase-1 (HO-1). This activation significantly improves neurological function in MCAO rats, reduces neuronal damage, inhibits ROS generation, and enhances the activities of superoxide dismutase and glutathione peroxidase (GSH-PX). Additionally, BYHWD restores mitochondrial membrane potential (MMP) and mitigates CIRI.66 Furthermore, the activation of the PKCε signaling pathway by BYHWD also activates nicotinamide phosphoribosyl transferase (Nampt), a key downstream target that maintains mitochondrial homeostasis. In turn, this, increases the activity of silent information regulator 5, providing a protective effect on mitochondrial function. Ultimately, these effects lead to improved cerebral infarct outcomes in the MCAO and reperfusion (MCAO/R) model by restoring MMP and reducing ROS, thereby alleviating CIRI.67 The active ingredient glycosides in BYHWD can regulate the Nrf2-mediated antioxidant stress pathway, thereby inhibiting neuronal pyroptosis in MCAO/R rats and exerting a neuroprotective effect in cerebral ischemia-reperfusion.68 Consequently, the regulation of Nrf2 targets by BYHWD may be attributed to the action of glycosides, although further experiments are necessary for verification. In addition to the calcium ion, BYHWD mediates the Nrf2-regulated Nrf2/GPX4 pathway, which affects ferroptosis in MCAO mice. BYHWD enhances the activity of Nrf2, GPX4 while reducing Keap1 levels and promoting Nrf2 nuclear translocation, thereby improving mitochondrial structure.69 Furthermore, BYHWD regulates iron metabolism by increasing GPX4 release, thus improving post-ischemic brain tissue injury.70 In summary, BYHWD confers robust protection against CIRI by coordinately activating the Nrf2 antioxidant network and its associated mitochondrial regulatory pathways. Through suppression of oxidative stress, and preservation of mitochondrial integrity, BYHWD demonstrates considerable potential as a multi-target neuroprotective strategy for IS.

VEGF

VEGF is a multifunctional growth factor that plays a crucial role in ischemic conditions. Within three hours post-ischemia, the expression level of VEGF in the ischemic penumbra region significantly increases, leading to vascular leakage.71 Notably, early administration of VEGF may exacerbate BBB permeability and expand the cerebral infarction area in ischemic rats.72 Consequently, VEGF expression is upregulated during the acute phase of IS. Furthermore, BYHW significantly alleviates cerebral edema and reduces cerebral infarction volume by inhibiting the activation of the VEGF pathway in the early stages of IS.73

VEGF also plays a dominant role in the brain by binding to phosphotyrosine kinase receptors fetal liver kinase (Flk).74 During CIRI, BYHWD upregulated the expression of VEGF, thereby promoting the migration of neural precursor cells (NPCs) to the ischemic brain region and facilitating neuronal differentiation.75 Moreover, BYHWD promotes VEGF by mediating mesenchymal stem cells (MSCs) exosomes, thereby enhancing cerebral angiogenesis.76 SIRT1 is also involved in the neuroprotective effects of BYHWD by VEGF. In MCAO rats, BYHWD targets the upregulation of SIRT1, subsequently activating the VEGF pathway, significantly improving the Neurological Function Score, and increasing the microvascular density.77 BYHWD can also significantly increase the expression of VEGF and Flk1 in the subventricular zone and cortex of ischemic brain tissue, thereby restoring neurological deficits.74 In summary, VEGF plays a pivotal role in promoting angiogenesis and improving microcirculation, significantly aiding the repair of ischemic brain tissue during BYHWD treatment for IS. However, more research is needed to clarify the long-term effects of VEGF modulation, as well as the optimal conditions for maximizing its neuroprotective potential without unwanted side effects.

Inflammasome

The inflammasome is a protein complex activated by initiator proteins like NLRP3 and AIM2The clustering of AIM2 or NLRP3 recruits the adaptor molecule apoptosis-associated speck-like protein containing a CARD (ASC), which subsequently recruits pro-caspases to facilitate their activation.78,79 Activation of AIM2 recruits ASC, which activates pro-caspases, leading to IL-1β release and Fas ligand (FasL) upregulation, triggering T cell apoptosis. BYHWD can ameliorate stroke-induced immunosuppression by downregulating Fas-dependent splenic T cell apoptosis triggered. This treatment effectively inhibits the expression of key proteins and factors within the AIM2/IL-1β/FasL/Fas axis, significantly reduces the size of cerebral infarction lesions, and alleviates histopathological damage in MCAO mice.80 Beyond AIM2, BYHWD protected against injury following delayed t-PA treatment by upregulating PGC-1α expression, thereby inhibiting the NLRP3 inflammasome and pyroptosis.81 In addition, glycosides can significantly inhibit the expression of NLRP3, ASC, pro-caspase-1, caspase-1, and IL-1β proteins, thereby suppressing the pyroptosis process of neurons after CIRI.82 And glycosides also regulate astrocyte exosome miR-378b_L +1 to reduce NLRP3 expression, thereby inhibiting neuronal pyroptosis.55 In summary, BYHWD can inhibit the AIM2 and NLRP3 inflammasomes, thereby improving neurological function scores and alleviating histopathological damage caused by MCAO. Further studies are required to pinpoint the exact molecular interactions and validate its clinical efficacy, particularly in human patients.

The Notch Signaling Pathway

The Notch signaling pathway plays a crucial role in the development of the nervous system and in the pathological processes that follow a stroke.83,84 This pathway is actively involved in astrocytes and microglia,85,86 where its activation significantly inhibits the differentiation of oligodendrocyte precursor cells (OPCs) following demyelinating injury.87 Research indicates that BYHWD can exert neuroprotective and reparative effects by modulating the Notch signaling pathway within glial cells. Specifically, BYHWD effectively inhibits the activation of the Notch signaling pathway in astrocytes and microglia, downregulating the expression of JAG1, Notch1, and NICD. This inhibition helps maintain the structural integrity of both gray and white matter, promotes remyelination, and protects the motor cortex and external capsule regions.88 Additionally, BYHWD effectively suppresses the Notch signaling pathway in OPCs, as evidenced by a reduction in the number of NG2/Notch1, NG2/NICD, and NG2/Hes5 positive cells. This suppression enhances the generation of oligodendrocytes and myelin repair while improving the structural reorganization of the internal capsule.89 In summary, BYHWD significantly improves motor dysfunction following a stroke by inhibiting the abnormal activation of the Notch signaling pathway in glial cells, promoting remyelination, facilitating structural recovery of the internal capsule, and protecting the motor cortex and external capsule regions.

The Others Pathway

BYHWD exerts therapeutic effects on IS through various other pathways. It regulates key targets like Aprt, Pde1b, and Gpd1, and modulates metabolic pathways such as glycerophospholipid metabolism and purine metabolism, restoring metabolic balance.90 Metabolomics show BYHWD restores stroke-related metabolic disorders, targeting folate, sphingolipid, and inositol phosphate metabolism.91 Metabolites like hippuric acid and lysophosphatidic acid reduce neuronal apoptosis via RhoA/Rock2 inhibition.92 Additionally, BYHWD inhibits NF-κB, reducing CXCL10-CXCR3 expression and NK cell infiltration, thereby improving ischemic outcomes.93 In terms of neuroplasticity, BYHWD enhances hippocampal-cortical connectivity via Sonic Hedgehog (Shh) signaling, promoting memory recovery.94,95 It also accelerates white matter repair by activating TREM2-ERK1/2 signaling, enhancing microglial phagocytosis and IGF1 secretion, which promotes oligodendrocyte proliferation and myelin regeneration.96 Despite these promising results, future research should focus on optimizing its application in diverse stroke models, evaluating long-term effects, and addressing any potential safety concerns.

BYHWD Improves IS by Neural Synaptic Plasticity

Synaptic plasticity in the temporal lobe is shaped by the activity of both presynaptic and postsynaptic regions. Without early intervention during stroke, dendrites degenerate, reducing synaptic efficiency and causing neuronal necrosis. Enhancing synaptic plasticity is crucial for neural recovery.97 BYHWD has been demonstrated to effectively enhance synaptic plasticity, as illustrated in Figure 2. Growth associated protein 43 (GAP-43) is recognized as a marker for axonal growth, while Synaptophysin (SYN) serves as a critical indicator of synaptic plasticity, facilitating the assessment of changes in the plasticity of axons and synapses. In IS rats, the protein levels of GAP-43 and SYN were significantly diminished; however, intervention with BYHWD effectively reversed this trend.98 Furthermore, BYHWD promotes the proliferation and differentiation of neural stem cells, thereby enhancing synaptic plasticity within brain tissue.99 Additionally, BYHWD upregulates the expression of the synaptic plasticity marker Postsynaptic Density-95 (PSD-95).100 Studies also show that BYHWD significantly upregulates the expression of PSD95 and SYN, inhibiting synaptic protein loss and preventing synaptic damage.101

Figure 2 BYHWD enhances IS by modulating the VEGF pathway and inflammasome pathways, as well as influencing NK, MSCs, NPCs and regulating synaptic plasticity.

Abbreviations: BYHWD, Buyang Huanwu Decoction; IS, Ischemic stroke; VEGF, vascular endothelial growth factor; NLRP3, Nod-like receptor family pyrin domain containing 3; NK, Natural killer; GAP-43, Growth Associated Protein 43; SYN, Synaptophysin; PSD-95, Postsynaptic Density-95; MSCs, Mesenchymal Stem Cells; NPCs, Neural precursor cells.

Studies have demonstrated that the cAMP/PKA/CREB pathway plays a critical role in enhancing the synaptic plasticity of damaged neurons. BYHWD enhances this pathway by upregulating synaptic proteins such as Syt1, Psd95, and Syn1, leading to increased dendritic spine density, improved synaptic plasticity, and thicker postsynaptic membranes with more synapses.97 Furthermore, research indicates that the components of BYHWD, calycosin-7-D-glucoside (CG) and formononetin-7-O-β-D-glucoside (FG), significantly enhance the expression level of the GAP-43.102 Additionally, the combination of BYHWD with exercise therapy results in a marked improvement in neurobehavioral deficits, significantly increasing the expression levels of SYN, GAP-43, and the cytoskeletal protein MAP-2, while preserving the integrity of synaptic ultrastructure and promoting neural rehabilitation.103 In summary, BYHWD demonstrates significant potential in improving neural plasticity and functional recovery after IS by regulating synaptic plasticity-related proteins and signaling transduction through multiple targets and pathways.

Preparations Related to BYHWD Improve IS

BYHWD is widely utilized in IS, and its derivatives and preparations have also demonstrated neuroprotective effects. For instance, the Hedysarum multijugum Maxim.-Chuanxiong rhizoma compound (HCC) is associated with the inhibition of phosphorylated PERK expression in the PERK pathway, upregulation of GRP78 protein, and reduction of CHOP expression levels. It exerts therapeutic effects by modulating multiple pathways, including endoplasmic reticulum stress, inflammation, and oxidative stress, thereby improving the neurobehavioral scores of IS rats and protecting neurons.104 Similarly, treatment with Xiaoshuan Enteric-Coated Capsule (XSECC) significantly upregulated NeuN protein expression on the 14th day post-stroke and generated CD34-positive capillaries in the peri-infarct region, ameliorating neuronal damage and endothelial cell injury. Additionally, XSECC treatment markedly reduced the cerebral infarct volume induced by permanent MCAO in IS, alleviated edema, and mitigated nerve fiber damage.105

QLC is a Chinese patented drug developed from BYHWD, with its active ingredients subjected to rigorous quality control. QLC has been clinically utilized in China for the treatment of IS.106 Research indicates that the primary components of QLC, including paeoniflorin, amygdalin, and calycosin-7-glucoside, demonstrate significant vasodilatory effects.107 QLC demonstrates a significant protective effect against ponatinib-induced IS. It effectively reduces the area of cerebral vascular embolism, enhances the staining intensity of red blood cells, and decreases the number of apoptotic brain cells. It also inhibits pro-apoptotic genes such as caspase-1, −2, and −3, while increasing the Bax/Bcl-2 ratio.108 QLC reduces the expression levels of recombinant purinergic receptor P2Y and G protein-coupled receptor P2Y12. It treats multi-infarct dementia (MID) by modulating the P2Y12/AC/cAMP pathway, thereby alleviating neuronal necrosis and cognitive dysfunction.109 In summary, BYHWD and its derivatives (such as HCC, XSECC, and QLC) exhibit multi-target and multi-dimensional neuroprotective and vascular repair effects in models of IS and its complications. They regulate pathological processes, including inflammatory responses, cell apoptosis, and platelet activation. These studies not only deepen the understanding of the modern pharmacological mechanisms of traditional formulations but also provide important evidence for the clinical translation and application of TCM compound preparations.

Table 1 Clinical Research of BYHWD in the Treatment of IS

Current Clinical Research Status of BYHWD in the Treatment of IS

Recent bibliometric analysis indicates that TCM in IS is continuously evolving, with active ingredients and compound formulas remaining major research hotspots.119 BYHWD has had its clinical value preliminarily validated in multiple studies, as illustrated in Table 1. It has been preliminarily validated in clinical studies, offering valuable insights for integrated IS management in both Chinese and Western medicine.110,120 Stroke patients are at higher risk for developing diabetes and epilepsy compared to the general population, and BYHWD significantly reduces the risk of these conditions, highlighting its potential in secondary stroke prevention.116,117 Furthermore, BYHWD has exhibited significant synergistic effects when used in combination therapy. A meta-analysis involving 902 patients revealed that BYHWD combined with acupuncture therapy significantly enhances clinical efficacy while reducing adverse reactions.114 Additional clinical studies also indicate that the combined conventional treatment (CT) also resulted in lower NIHSS, and CSS scores, improves stroke symptoms and post-stroke sequelae.121 Moreover, the combination with rt-PA intravenous thrombolysis produced superior therapeutic outcomes. A randomized controlled trial (RCT) showed greater improvements in NIHSS scores and hemodynamic parameters compared to monotherapy, with a reduction in oxidative stress via activation of the Keap1–Nrf2/ARE pathway.118 3,683 patients with IS in the recovery phase revealed that the combination of BYHWD and conventional therapy significantly improved activities of daily living (ADL), and demonstrating greater efficacy than monotherapy.115 Similarly, QLC showed effectiveness in functional rehabilitation. Among 2,302 participants, the combination therapy resulted in significantly greater improvements in modified Rankin Scale, NIHSS, and Barthel Index scores after 24 weeks compared with controls.106 Evidence-based analysis indicates that Qilong Capsules combined with conventional Western medicine improve quality of life with good economic feasibility, achieving an overall Grade A clinical value.122

In post-stroke sequelae, BYHWD has demonstrated both efficacy and safety. A meta-analysis of 2,527 patients showed that BYHWD combined with conventional therapy improved Clinical Efficacy Rate and enhanced Fugl-Meyer Assessment motor function, with no reported adverse events.113 Furthermore, this formula shows promise in the treatment of post-stroke depression (PSD). An analysis of 1,242 patients showed that a 4-week course of BYHWD treatment was most effective for PSD, while also ensuring good safety.111 Overall, BYHWD improves neurological deficits and daily living abilities in ischemic stroke patients and exhibits synergistic effects in combination therapy. Future studies should elucidate its multi-target mechanisms and confirm long-term efficacy and safety through large-scale clinical trials, thereby facilitating broader and standardized clinical application.

Conclusion

BYHWD is widely used for the treatment of IS and its sequelae. We summarized the pharmacological effects of its seven constituent herbs and their active components in IS. Among these, Astragalus saponins, FA, baicalein, and HSYA appear to contribute substantially to its therapeutic effects. Experimental studies suggest BYHWD exerts neuroprotective actions through multi-pathway and multi-target regulation, involving pathways such as PI3K-Akt, autophagy, Nrf2, VEGF, inflammasome, Notch, NF-κB, and ferroptosis. These effects are associated with reduced oxidative stress, inflammation, apoptosis, and preservation of BBB integrity. In addition, BYHWD has been reported to alleviate CIRI and improve neurological deficits. Some studies also indicate its potential role in modulating synaptic plasticity and promoting neural repair, which may be relevant for long-term functional recovery. From a translational perspective, research on BYHWD and its derivatives has increased, with progress in dosage form optimization supporting its further clinical exploration.

Despite these findings, the clinical application of BYHWD in IS remains challenging. Most mechanistic studies are limited to preclinical ischemic models, and only a small number of formulations have progressed toward robust clinical validation. Although some clinical reports suggest potential rehabilitative benefits, there are certain methodological flaws in TCM research. It often lacks large-scale, rigorous randomized controlled trials, limiting scientific evidence for treatment efficacy. The absence of standardized, quantifiable outcome measures in evaluating TCM therapies affects the comparability of studies. Common limitations include lack of blinding, short follow-up periods, and insufficient reporting of adverse events. Current data are therefore insufficient to support widespread clinical adoption. An additional challenge lies in the complex, multi-component nature of BYHWD, which complicates the identification of components most relevant to IS. Compounds such as HSYA, paeoniflorin, albiflorin, lactiflorin, astragaloside IV, baicalein, calycosin, and formononetin have been frequently identified as potentially important contributors. However, most evidence supporting their roles is derived from in silico analyses or preclinical models. Experimental and clinical validation remains insufficient to determine which components are essential, their relative contributions, or whether specific components or simplified formulations could achieve comparable therapeutic effects. The current issues further hinders the identification of optimal dosing and clinical relevance.

Recent integrative approaches combining metabolomics have provided valuable insights into the mechanisms of BYHWD in CIRI. Future research should focus on component-based clinical studies to clarify the key bioactive substances in BYHWD that contribute to its therapeutic effects in IS. Larger, multicenter, well-designed RCTs are necessary to establish robust evidence for efficacy and safety of BYHWD in IS treatment. Current studies suffer from methodological limitations, including small sample sizes, lack of blinding, and short follow-up periods. Adherence to reporting guidelines such as SYRCLE and ARRIVE will be crucial to improve the quality of future research and enable reliable clinical translation.123 Additionally, targeted drug delivery strategies, particularly the use of extracellular vesicles (EVs),124 offer new potential for treating IS. EVs can efficiently deliver Astragaloside IV and Paeoniflorin to the brain, improving CIRI. The advancements in drug delivery systems could significantly enhance the therapeutic efficacy of BYHWD and should accelerate clinical trials to provide more treatment options for IS.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Funding

The authors declare that the research and/or publication of this article was funded by the Basic and Applied Basic Research Foundation of Guangdong Province [2021B1515140040]; the National Training Program for Heritage Talents of Traditional Chinese Medicine Characteristic Techniques [T202348322005]; and the Liu Zai Dongguan Renowned Chinese Medicine Expert Heritage Studio [Dongwei Han [2024] No. 210].

Disclosure

The authors declare that they have no known competing interests in this paper.

References

1. Cheng J, Zheng Y, Cheng F. et al. Different roles of astrocytes in the blood-brain barrier during the acute and recovery phases of stroke. Neural Regen Res. 2026;21(4):1359–16. doi:10.4103/nrr.Nrr-d-24-01417

2. Zhai Z, Su PW, Ma LY, et al. Progress on traditional Chinese medicine in treatment of ischemic stroke via the gut-brain axis. Biomed Pharmacother. 2023;157:114056. doi:10.1016/j.biopha.2022.114056

3. Ma Y, Wang X, Li Y, et al. Mechanisms Associated with Mitophagy and Ferroptosis in Cerebral Ischemia-reperfusion Injury. J Integr Neurosci. 2025;24(3):26458. doi:10.31083/jin26458

4. Li Y, Miao L, Guo R, et al. To explore the regulatory effect of Buyang Huanwu Decoction on cerebral infarction based on quantitative proteomics. J Proteomics. 2023;277:104850. doi:10.1016/j.jprot.2023.104850

5. Li XH, Yin FT, Zhou XH, et al. The Signaling Pathways and Targets of Natural Compounds from Traditional Chinese Medicine in Treating Ischemic Stroke. Molecules. 2022;27(10):3099. doi:10.3390/molecules27103099

6. Wang N, Chen J, Dang Y, et al. Research progress of traditional Chinese medicine in the treatment of ischemic stroke by regulating mitochondrial dysfunction. Life Sci. 2024;357:123045. doi:10.1016/j.lfs.2024.123045

7. Jiang X, Andjelkovic A V, Zhu L, et al. Blood-brain barrier dysfunction and recovery after ischemic stroke. Prog Neurobiol. 2018;163-164:144–171. doi:10.1016/j.pneurobio.2017.10.001

8. Yin X, Li S, Wang J, et al. Research progress of active compounds from traditional Chinese medicine in the treatment of stroke. Eur J Med Chem. 2025;291:117599. doi:10.1016/j.ejmech.2025.117599

9. Ning B, Zhu X, Wu X, et al. Efficacy of different traditional Chinese medicine decoctions in the treatment of ischemic stroke: a network meta-analysis. Front Pharmacol. 2024;15:1486458. doi:10.3389/fphar.2024.1486458

10. Mu Q, Liu P, Hu X, et al. Neuroprotective effects of Buyang Huanwu decoction on cerebral ischemia-induced neuronal damage. Neural Regen Res. 2014;9(17):1621–1627. doi:10.4103/1673-5374.141791

11. Sun J, Bi Y, Guo L, et al. Buyang Huanwu Decoction promotes growth and differentiation of neural progenitor cells: using a serum pharmacological method. J Ethnopharmacol. 2007;113(2):199–203. doi:10.1016/j.jep.2007.05.018

12. Jin C, Kwon S, Cho SY, et al. A Systematic Review and Meta-Analysis of the Effects of Herbal Medicine Buyang Huanwu Tang in Patients with Poststroke Fatigue. Evid Based Complement Alternat Med. 2021;2021:4835488. doi:10.1155/2021/4835488

13. Guo Q, Zhong M, Xu H, et al. A Systems Biology Perspective on the Molecular Mechanisms Underlying the Therapeutic Effects of Buyang Huanwu Decoction on Ischemic Stroke. Rejuvenation Res. 2015;18(4):313–325. doi:10.1089/rej.2014.1635

14. Shen J, Zhu Y, Huang K, et al. Buyang Huanwu Decoction attenuates H2O2-induced apoptosis by inhibiting reactive oxygen species-mediated mitochondrial dysfunction pathway in human umbilical vein endothelial cells. BMC Complement Altern Med. 2016;16:154. doi:10.1186/s12906-016-1152-7

15. Hsu WH, Shen YC, Shiao YJ, et al. Combined proteomic and metabolomic analyses of cerebrospinal fluid from mice with ischemic stroke reveals the effects of a Buyang Huanwu decoction in neurodegenerative disease. PLoS One. 2019;14(1):e0209184. doi:10.1371/journal.pone.0209184

16. Zhao LD, Wang JH, Jin GR, et al. Neuroprotective effect of Buyang Huanwu decoction against focal cerebral ischemia/reperfusion injury in rats--time window and mechanism. J Ethnopharmacol. 2012;140(2):339–344. doi:10.1016/j.jep.2012.01.026

17. Shen YC, Lu CK, Liou KT, et al. Common and unique mechanisms of Chinese herbal remedies on ischemic stroke mice revealed by transcriptome analyses. J Ethnopharmacol. 2015;173:370–382. doi:10.1016/j.jep.2015.07.018

18. Hong Y, Ko G, Jeon YJ, et al. Neuroprotective Efficacy of Astragalus mongholicus in Ischemic Stroke: antioxidant and Anti-Inflammatory Mechanisms. Cells. 2025;14(2):117. doi:10.3390/cells14020117

19. Li R, Lou Q, Ji T, et al. Mechanism of Astragalus mongholicus Bunge ameliorating cerebral ischemia-reperfusion injury: based on network pharmacology analysis and experimental verification. J Ethnopharmacol. 2024;329:118157. doi:10.1016/j.jep.2024.118157

20. Xu L, Xu XY, Hou XQ, et al. Adjuvant therapy with Astragalus membranaceus for post-stroke fatigue: a systematic review. Metab Brain Dis. 2020;35(1):83–93. doi:10.1007/s11011-019-00483-4

21. Liu P, Zhao H, Luo Y. Anti-Aging Implications of Astragalus membranaceus (Huangqi): a Well-Known Chinese Tonic. Aging Dis. 2017;8(6):868–886. doi:10.14336/ad.2017.0816

22. Wang Y, Liu X, Hu T, et al. Astragalus saponins improves stroke by promoting the proliferation of neural stem cells through phosphorylation of Akt. J Ethnopharmacol. 2021;277:114224. doi:10.1016/j.jep.2021.114224

23. Li Z, Hu E, Zheng F, et al. The effects of astragaloside IV on gut microbiota and serum metabolism in a mice model of intracerebral hemorrhage. Phytomedicine. 2023;121:155086. doi:10.1016/j.phymed.2023.155086

24. Zhu XH, Yu X, Kong XW, et al. Insight of action mechanism of Astragaloside IV for relieving of cerebral ischemic injury in a rat model of middle cerebral artery occlusion reperfusion via proteomics and network pharmacology. J Nat Med. 2025;79(3):591–607. doi:10.1007/s11418-025-01892-9

25. Wang M, Zhu W, Guo Y, et al. Astragalus polysaccharide treatment relieves cerebral ischemia‒reperfusion injury by promoting M2 polarization of microglia by enhancing O-GlcNAcylation. Metab Brain Dis. 2024;40(1):16. doi:10.1007/s11011-024-01420-w

26. Tang X, Xie S, Wang H, et al. The combination of Astragalus membranaceus and ligustrazine mitigates cerebral ischemia-reperfusion injury via regulating NR2B-ERK/CREB signaling. Brain Behav. 2023;13(2):e2867. doi:10.1002/brb3.2867

27. Cheng CY, Huang HC, Kao ST, et al. Angelica sinensis extract promotes neuronal survival by enhancing p38 MAPK-mediated hippocampal neurogenesis and dendritic growth in the chronic phase of transient global cerebral ischemia in rats. J Ethnopharmacol. 2021;278:114301. doi:10.1016/j.jep.2021.114301

28. Zhang S, Luo HT, Fan KX, et al. Chirality Determination and Anti-inflammatory Activity of Phthalide Monomers in Angelica sinensis. J Nat Prod. 2025;88(7):1581–1590. doi:10.1021/acs.jnatprod.5c00263

29. Cheng CY, Kao ST, Lee YC. Angelica sinensis extract protects against ischemia-reperfusion injury in the hippocampus by activating p38 MAPK-mediated p90RSK/p-Bad and p90RSK/CREB/BDNF signaling after transient global cerebral ischemia in rats. J Ethnopharmacol. 2020;252:112612. doi:10.1016/j.jep.2020.112612

30. Cheng CY, Ho TY, Lee EJ, et al. Ferulic acid reduces cerebral infarct through its antioxidative and anti-inflammatory effects following transient focal cerebral ischemia in rats. Am J Chin Med. 2008;36(6):1105–1119. doi:10.1142/s0192415x08006570

31. Mao Z, Tian L, Liu J, et al. Ligustilide ameliorates hippocampal neuronal injury after cerebral ischemia reperfusion through activating PINK1/Parkin-dependent mitophagy. Phytomedicine. 2022;101:154111. doi:10.1016/j.phymed.2022.154111

32. Han Y, Chen Y, Zhang Q, et al. Overview of therapeutic potentiality of Angelica sinensis for ischemic stroke. Phytomedicine. 2021;90:153652. doi:10.1016/j.phymed.2021.153652

33. Wen T, Xin G, Zhou Q, et al. Investigation into the Potential Mechanism of Radix Paeoniae Rubra Against Ischemic Stroke Based on Network Pharmacology. Nutrients. 2024;16(24):4409. doi:10.3390/nu16244409

34. Zhao F, Peng C, Li H, et al. Paeoniae Radix Rubra extract attenuates cerebral ischemia injury by inhibiting ferroptosis and activating autophagy through the PI3K/Akt signalling pathway. J Ethnopharmacol. 2023;315:116567. doi:10.1016/j.jep.2023.116567

35. Chen X, Wang Y, Ma Y, et al. To explore the Radix Paeoniae Rubra-Flos Carthami herb pair’s potential mechanism in the treatment of ischemic stroke by network pharmacology and molecular docking technology. Medicine. 2021;100(49):e27752. doi:10.1097/md.0000000000027752

36. Gu J, Chen J, Yang N, et al. Combination of Ligusticum chuanxiong and Radix Paeoniae ameliorate focal cerebral ischemic in MCAO rats via endoplasmic reticulum stress-dependent apoptotic signaling pathway. J Ethnopharmacol. 2016;187:313–324. doi:10.1016/j.jep.2016.04.024

37. Luo FH, Zeng FF, Ren X, et al. Pheretima: a system review of zoology, traditional applications, processing technology, chemical composition, pharmacologic activities, quality control and toxicity. J Ethnopharmacol. 2025;351:120093. doi:10.1016/j.jep.2025.120093

38. Zhao L, Yin M, Wang M, et al. Earthworm extract improves cerebral ischemia-reperfusion injury through regulating microglia polarization and promoting cerebral angiogenesis in vitro and in vivo. Brain Res. 2025;1861:149721. doi:10.1016/j.brainres.2025.149721

39. Sun ZY, Wang FJ, Guo H, et al. Shuxuetong injection protects cerebral microvascular endothelial cells against oxygen-glucose deprivation reperfusion. Neural Regen Res. 2019;14(5):783–793. doi:10.4103/1673-5374.249226

40. Kong Q, Niu Y, Feng H, et al. Ligusticum chuanxiong Hort.: a review of its phytochemistry, pharmacology, and toxicology. J Pharm Pharmacol. 2024;76(11):1404–1430. doi:10.1093/jpp/rgae105

41. Lim C, Lim S, Moon SJ, et al. Neuroprotective effects of methanolic extract from Chuanxiong Rhizoma in mice with middle cerebral artery occlusion-induced ischemic stroke: suppression of astrocyte- and microglia-related inflammatory response. BMC Complement Med Ther. 2024;24(1):140. doi:10.1186/s12906-024-04454-w

42. Wang M, Yao M, Liu J, et al. Ligusticum chuanxiong exerts neuroprotection by promoting adult neurogenesis and inhibiting inflammation in the hippocampus of ME cerebral ischemia rats. J Ethnopharmacol. 2020;249:112385. doi:10.1016/j.jep.2019.112385

43. Ge Q, Wang Z, Yu J, et al. Chuanxiong Rhizoma regulates ferroptosis and the immune microenvironment in ischemic stroke through the JAK-STAT3 pathway. Sci Rep. 2024;14(1):31224. doi:10.1038/s41598-024-82486-5

44. Liang Y, Wang L. Carthamus tinctorius L.: a natural neuroprotective source for anti-Alzheimer’s disease drugs. J Ethnopharmacol. 2022;298:115656. doi:10.1016/j.jep.2022.115656