STX1A is a member of the syntaxin family and is encoded on human chromosome 7q11.23. It comprises 288 amino acids and is one of two isoforms of Syntaxin1, the other being Syntaxin1B (STX1B) (16). STX1A is primarily localized on the plasma membrane. It has four major structural components: An N-terminal peptide (N-peptide), an N-terminal regulatory domain (Habc), a SNARE domain (also known as the H3 domain), and a C-terminal transmembrane domain (TMD) (17) (Fig. 1). The N-peptide is connected to the Habc domain by a flexible region, and the Habc domain is linked to the H3 domain through a linker region. Additionally, the H3 domain is connected to the TMD by a short polybasic juxtamembrane domain. The Habc domain (18) is a highly conserved domain composed of three antiparallel α-helices and plays a crucial role in synaptic transmission in mammals (18). Moreover, the Habc domain interacts with key proteins, including synaptotagmin-1 (Syt1) (19), voltage-gated calcium channels (VGCCs), and Munc18-1, thereby facilitating the precise recruitment of the STX1A-Munc18-1 complex to the active zone (AZ) (20). The SNARE domain of STX1A contains a highly conserved sequence of 60-70 residues with heptanucleotide repeats (21). Significantly, STX1A contributes a Qa-SNARE motif to the SNARE complex, assembling with synaptosomal-associated protein of 25 kDa (SNAP-25; Qbc-SNARE motifs) and synaptobrevin (VAMP; R-SNARE motif) in a 1:1:1 ratio to form a stable four-helix bundle, a structural prerequisite for vesicle fusion and neurotransmitter exocytosis (22). The Habc domain can also interact with its own SNARE motif, forming a ‘closed’ conformation that regulates STX1A activity, a process modulated by its interaction with neuronal Sec1 (nSec1; also known as rbSec1 or Munc18-1) (23). Furthermore, the C-terminal TMD of STX1A primarily anchors the membrane through its hydrophobic region.

STX1A is a crucial core protein involved in vesicle fusion, primarily contributing to SNARE complex assembly (24). In mammals, vesicle trafficking is the primary transport mechanism in eukaryotic cells, enabling processes such as endocytosis and exocytosis through membrane fusion. This fusion is facilitated by the formation of SNARE complexes (25). SNARE proteins are categorized based on their membrane localization: t-SNAREs are found on target membranes, while v-SNAREs are located on vesicular membranes. Moreover, VAMP belongs to v-SNARE, while SNAP-25 and STX1A are t-SNAREs (26). The mechanism of plasma membrane vesicle fusion in neuronal cells holds significant physiological importance. Consequently, numerous severe neurological diseases are associated with the improper localization of vesicle fusion-related proteins (27).

In the synapse, a small number of vesicles reside at specific sites in the presynaptic membrane AZ. By contrast, most vesicles are transported to areas near the cell membrane after synthesis, forming a reserve pool. Neurotransmitter release by neuronal exocytosis (Fig. 2) can be divided into several steps, including vesicle mobilization, docking, priming, fusion, and recycling (28). During rest, synaptic vesicles in the readily releasable pool within the AZ participate in neurotransmitter release. In addition, the AZ is enriched in cytoskeletal and scaffold proteins, forming a dense matrix that facilitates the anchoring, preparation, and rapid release of synaptic vesicles. In neuronal and endocrine cells, priming is a necessary rate-limiting step in secretion, in which vesicles are released only after priming. Moreover, SNARE proteins mediate vesicle priming and membrane fusion (29). In the resting state, STX1A is in a ‘closed’ conformation and cannot participate in the assembly of the SNARE complex. Following an action potential burst, a signal spreads along the axon to the presynaptic membrane, depolarizing the axon. Subsequently, this opens VGCCs, triggering Ca²⁺ influx. Elevated intracellular Ca²⁺ facilitates the recruitment of primed vesicles from the reserve pool to AZ through interactions with Rab proteins (30), RIM, and Munc13. These vesicles are tethered to the plasma membrane, forming trans-SNARE complexes, a process known as vesicle priming (31). The influx of Ca²⁺ binds to synaptotagmin (a Ca²⁺ sensor), with the assistance of the complexin protein, thereby interacting with STX1A to induce an open conformation. Consequently, this promotes SNARE complex assembly through a series of ordered and continuous reactions. In the priming phase, STX1A and SNAP-25 form a t-SNARE complex on the target membrane, which then assembles with VAMP2 (32,33) (on the vesicle membrane), forming a trans-SNARE complex or SNAREpin. This complex forms through a zipper-like mechanism from the N-terminal to the C-terminal regions, pulling the vesicle and plasma membranes into close apposition and providing energy for lipid bilayer fusion (34). Subsequently, primed vesicles are drawn toward the plasma membrane and fuse with it. During this process, the trans-SNARE complex is converted into cis-SNARE complexes, which form a fusion pore and release neurotransmitters from synaptic vesicles into the synaptic cleft (35). In addition, changes in calcium ion concentration directly affect the amount of neurotransmitter released and are necessary for vesicle fusion with the presynaptic membrane (36). Following membrane fusion, the resulting cis-SNARE complexes are disassembled by the AAA+ ATPase NSF (37) and its cofactor α-soluble NSF attachment protein (α-SNAP). This ensures that SNARE can be recycled for the next round of fusion, thereby maintaining the efficiency of synaptic transmission (Fig. 3).

In addition to affecting neurotransmitter release, STX1A plays an indispensable part in neuronal development, synaptic plasticity, and ion channel regulation. Fuschini et al (38) demonstrated that STX1A mediates the release of brain-derived neurotrophic factor, thereby regulating neuronal axon growth, synapse formation, and cognitive function. Notably, synaptic plasticity underpins higher neural functions, including learning and memory. As such, research indicates that STX1A plays a significant role in long-term potentiation and low-latency inhibition (39,40). Using the STX1A gene-mutation knock-in mouse model, paired-pulse facilitation and enhanced short-term neuronal plasticity (41) have been observed. In the striatum, a previous study has also found that STX1A expression is correlated with the acquisition of dopamine (DA)-related reward learning (42). Furthermore, a preliminary study discovered that STX1A interacts with ion channels (43). Consequently, the two conserved cysteine residues in the transmembrane region of STX1A directly interact with VGCCs, thereby modulating calcium influx and the excitatory coupling of neurotransmitters (44). In addition, STX1A binds to Kv2.1 (a voltage-gated potassium channel) to regulate cellular excitability (45). Thus, these roles suggest that STX1A maintains synaptic activity and functions as a key regulator in neuronal circuit remodeling.

SM family proteins (46) are essential auxiliary factors in membrane fusion and are involved in nearly all vesicular trafficking events. Munc18-1 (also known as STXBP1) is a key member of the SM family and is the primary regulatory partner of STX1A. It controls vesicle membrane fusion by modulating the conformational states of STX1A as it transitions between open and closed conformations. When Munc18-1 binds to the Habc domain of free STX1A, it stabilizes the monomeric STX1A in a closed, inactive conformation. In this state, the Habc domain interacts with the SNARE motif, forming a closed structure that is enveloped by the arched interface of the domains 1 and 3a of Munc18-1. As a result, this configuration prevents premature SNARE complex formation and inhibits vesicle fusion. Moreover, this mechanism ensures proper STX1A folding and avoids erroneous interactions that could generate off-pathway SNARE assemblies, thereby maintaining the precision of neurotransmitter release. Upon activation by the MUN domain of Munc13, Munc18-1 shifts its interaction to engage the N-terminal region of STX1A. This conformational switch promotes the open state of STX1A, facilitating its assembly with SNAP-25(47) and VAMP2(48) into a ternary SNARE complex (49). Finally, Munc18-1 and Munc13 are released from the template complex. Upon doing so, the three SNARE proteins are correctly assembled into a trans-SNARE complex, and membrane fusion is initiated (50). Notably, knockout experiments have shown that Munc18-1-deficient mice exhibit a complete loss of neurotransmitter secretion, despite normal synapse formation, underscoring the indispensable role of Munc18-1 in exocytosis (51).

Complexin (also known as synaphin) is a small cytosolic protein that acts as a clamp during the vesicle fusion process. It contains an N-terminal domain, an accessory α-helix, a central α-helix, and a C-terminal domain (52). Notably, complexin interacts with STX1A in two distinct modes: i) Mode 1: Complexin-1 (Cpx1), the isoform predominantly expressed in synapses, inserts its central α-helix antiparallel into the groove between VAMP2 and STX1A, stabilizing the vesicle in a semi-fused state and preventing premature fusion. ii) Mode 2: Upon Ca²⁺ binding, Syt1 competes with complexin for binding to STX1A via its C2B domain, relieving the inhibitory effect of complexin and initiating rapid fusion (53).

In complexin-knockdown mice, both spontaneous and evoked neurotransmitter release, including asynchronous and delayed modes, were significantly reduced. This supports the critical regulatory role of complexin in synaptic transmission (54).

Synaptotagmin is a synaptic vesicle protein evolutionarily conserved across species. It comprises an N-terminal single TMD, an unstructured linker region, and two cytoplasmic protein kinase C-like C2 domains (C2A and C2B) (53). The C2B domain has a high affinity for Ca²⁺ and is primarily responsible for triggering vesicle-plasma membrane fusion. By contrast, the C2A domain contributes to vesicle docking and mobility. Syt1, the principal isoform in synapses, serves as a Ca²⁺ sensor during neurotransmission. Upon Ca²⁺ influx, Syt1 binds phospholipids through its C2 domains, promoting membrane fusion. In vitro experiments have shown that Syt1 can dock vesicles by binding to STX1A/SNAP-25 receptor complexes, further emphasizing its central role in Ca²⁺-dependent neurotransmitter release (55).

ADHD is a common neurodevelopmental disorder that primarily affects school-age children and adolescents. It is characterized by inattention, hyperactivity, and impulsivity (64). ADHD is suggested to arise from complex interactions among genetic, neurobiological, and environmental factors. Although its exact pathogenesis remains unclear, genome-wide association studies (GWAS) indicate a strong genetic component, particularly involving genes encoding components of the SNARE complex (65). While no single gene has been found to account for ADHD, the interaction between polygenic susceptibility and environmental factors has been proven to increase the risk of ADHD (66). Genetic association studies also provide initial support for a relationship between STX1A and ADHD susceptibility. Wang et al (9) found that STX1A variations increase susceptibility to ADHD in Chinese Han children. Similar findings have been reported in adult populations, linking STX1A polymorphisms to ADHD (67). Furthermore, neuropsychopharmacological evidence suggests that ADHD stems from neurotransmitter system dysfunction (68), particularly imbalances in dopaminergic and noradrenergic systems (40). Furthermore, imbalances in these systems may lead to inattention and hyperactivity.

The most commonly prescribed treatments of ADHD are DA agonists and norepinephrine (NE) agonists, both of which effectively improve the symptoms of ADHD. Given the essential role of STX1A in synaptic vesicle exocytosis, reduced expression may result in insufficient DA release, contributing to ADHD symptoms. Additionally, STX1A regulates DA transporter (DAT) activity, which is responsible for DA reuptake and synaptic clearance (69). Moreover, DAT mediates the reuptake of DA by removing it from the synaptic cleft and returning it to presynaptic neurons. Thus, it modulates the concentration of DA in the synaptic cleft, thereby terminating DA signal transduction and ensuring proper nervous system function. Notably, STX1A mutations may exacerbate ADHD by enhancing DAT reuptake (70). Similarly, NE transporter (NET) inhibitors and α2-adrenergic receptor agonists are effective in ADHD treatment. Methylphenidate (MPH) has been shown to improve the symptoms of ADHD by inhibiting the reuptake of DA and NE through its action on the DAT and NET (71). Atomoxetine (ATX), as a selective NE reuptake inhibitor, is a non-stimulant medication commonly used in clinical practice for the treatment of ADHD. It improves cognitive function by modulating NE and indirectly enhancing DA signaling in the prefrontal cortex (68). A pharmacogenetic study assessed the therapeutic response to immediate-release (IR)-MPH and its association with genes involved in the SNARE complex in the treatment of ADHD. The findings indicated that SNARE complexes mediate the response to commonly prescribed ADHD medications (71). Mishima et al (39) also revealed that STX1A modulates noradrenaline transmission by regulating dense-core vesicle secretion, further underscoring its role in ADHD pathogenesis. Notably, the interplay between these two mechanisms may work in concert to ultimately disrupt DA and NE homeostasis, thereby increasing susceptibility to ADHD. Genetic association studies have mostly focused on Chinese Han populations, limiting generalizability (9). However, clinical pharmacological research confirms the functional relevance of the STX1A-associated pathway (68). This implies that modulating presynaptic release capacity influences ADHD treatment outcomes. Consequently, therapies targeting STX1A hold promise for improving the clinical management of ADHD by modulating dopaminergic and noradrenergic systems.

ASD encompasses a range of neurodevelopmental disorders characterized by deficits in social communication, restricted interests, and repetitive behaviors (72). Similar to ADHD, ASD is considered to result from the interplay between genetic predisposition and environmental influences (73). STX1A-deficient animal models display behavioral phenotypes analogous to human ASD, such as impaired fear memory, reduced latent inhibition, and abnormal social behavior (74,75). Beyond core ASD symptoms, patients with ASD may also experience central nervous system symptoms such as epilepsy, intellectual disability, and hyperactivity. Moreover, STX1A mutations in ASD include splice-site mutations, missense mutations, and frameshift variants, which lead to haploinsufficiency, impaired synaptic plasticity, and dopaminergic and serotonergic [5-hydroxytryptamine (5-HT)] disorders. Recently, Luppe et al (10) reported two novel heterozygous missense mutations in STX1A, which may perturb SNARE complex assembly or hinder the interaction between STX1A and STX1A-binding proteins. These two patients with epilepsy and ASD features suggest that the dysfunction of STX1A may be the main pathogenic mechanism for some patients with ASD. Notably, it also suggests that ASD shares common pathogenic pathways with epilepsy and ADHD (76). Additionally, Cartier et al (77) described a rare ASD-associated hypophosphorylated STX1A mutant that reduces DAT-mediated reverse transport and is implicated in ASD pathogenesis. Moreover, abnormalities in serotonergic transmission are common in ASD, and STX1A directly interacts with the serotonin transporter (5-HTT), modulating its localization and function (78). Genetic studies also indicate that STX1A polymorphisms, including single-nucleotide polymorphisms (SNPs) rs4717806 and rs941298, are associated with Asperger's syndrome (79). However, these genetic findings do not imply that most ASD cases are driven by STX1A defect; the alterations of STX1A in ASD show a high degree of heterogeneity. A study in Japan reported elevated STX1A mRNA expression in lymphocytes from individuals with high-functioning autism (80). Furthermore, increased STX1A expression was observed in the hippocampus of mice prenatally exposed to bisphenol A (BPA), a model for ASD, accompanied by impaired synaptic plasticity (57). Conversely, a study by Al-Ayadhi et al (81) investigated the effects of auditory integration training (AIT) in children with ASD. It evaluated changes in plasma STX1A protein levels following the intervention and their correlation with improvements in ASD symptoms (81). The study observed a significant increase in plasma STX1A levels following AIT, accompanied by meaningful enhancements in behavioral, social, and sensory processing scores (81). Thus, STX1A levels may be associated with ASD symptomatology, and plasma STX1A could potentially serve as a diagnostic biomarker for the disorder. Moving forward, restoring or modulating STX1A function in the brain may offer a novel therapeutic direction for ASD.

Notably, reports on STX1A expression in ASD are inconsistent, with both increased and decreased levels described across studies (57,77,80,81). Several factors may account for this discrepancy. At the genetic level, mutations in STX1A exhibit heterogeneity in both genotype and clinical manifestations. Loss-of-function mutations, such as frameshift mutations or splice-site variants that lead to haploinsufficiency) reduce the effective STX1A dosage. By contrast, regulatory variants or compensatory responses may yield apparent upregulation at the mRNA level. From a biological perspective, STX1A expression is highly dependent on environmental factors. It varies across brain regions (such as the frontal lobe and hippocampus), cell types (including excitatory and inhibitory neurons), and critical windows of neural development. Moreover, most studies use peripheral tissues or homogenate samples, which cannot capture this spatial and cell-specificity. Furthermore, technical limitations, such as the imperfect correlation between mRNA levels and functional protein activity, and confounding environmental exposures (such as BPA), introduce additional variability across studies. Consequently, the reported inconsistencies reflect not contradiction but rather the interplay of genetic heterogeneity, clinical heterogeneity, and methodological limitations. Thus, future studies integrating genotype-stratified cohorts, highly specific transcriptomics, and functional validation are needed to elucidate the role of STX1A across subtypes of ASDs.

Williams-Beuren syndrome (WS) is a rare genetic neurodevelopmental disorder characterized by a hemizygous deletion at 7q11.23. WS can affect multiple systems, particularly the nervous, cardiovascular, endocrine, and digestive systems. It leads to clinical manifestations of neurological abnormalities such as intellectual disability, excessive sociability, and attention-deficit. Notably, the STX1A gene, within the WS critical region, has been identified as a strong candidate for WS and may play a significant role in the neurodevelopment of the disease (82). A previous study demonstrated that STX1A gene transcript levels were significantly correlated with intellectual functioning in patients with WS (83). However, current research on STX1A in WS remains limited. Moreover, its precise pathogenic mechanism remains unclear.

Epilepsy is a common heterogeneous neurological disorder, whose main feature is the abnormal discharge of neurons leading to recurrent, paroxysmal, and transient dysfunction of the central nervous system (84). In the past decade, growing evidence has highlighted the pivotal role of synaptic protein-encoding genes in epilepsy pathogenesis (85). Among these, pathogenic variants affecting the SNARE complex and its regulatory proteins have been incorporated into the emerging concept of ‘SNAREopathies’ (SNARE-related disease spectrum), which helps explain epilepsy and other neurodevelopmental disorders arising from impaired presynaptic release mechanisms (86,87). While both isoforms, STX1A and STX1B, play roles in vesicle fusion, they exhibit distinct expression patterns. In knockout mouse models, STX1A and STX1B exhibit partial functional compensation. However, double knockout of these isoforms results in embryonic lethality due to the complete loss of synaptic vesicle fusion (18). Notably, the role of STX1B gene mutations in epileptic seizures has been extensively studied (87). By contrast, research on the association between STX1A mutations and the development of epilepsy is relatively limited. Recent human genetic studies have provided direct support for the association between STX1A and epilepsy. In 2023, Luppe et al (10) reported that a missense mutation in the STX1A gene leads to STX1A-related developmental and epileptic encephalopathy (10). In addition to rare variants, population-based genetic studies have identified statistical associations between common STX1A polymorphisms and cryptogenic epilepsy (88). For instance, in a North Indian population, SNPs in VAMP2 and STX1A were associated with cryptogenic epilepsy (88). However, broader population-level validation of these associations remains limited.

Experimental and clinical evidence further suggests that STX1A may contribute to epileptogenesis by modulating excitatory neurotransmission and neuronal excitability. Notably, dysregulation of glutamatergic signaling represents a key mechanism underlying seizure generation (89), indicating that disruption of presynaptic release machinery alters excitatory synaptic strength. A previous study using septic rat models revealed a significant reduction in STX1A and Munc18-1 expression in the hippocampus, correlating with impaired glutamate release (90). Another study demonstrated that STX1A reduces cell surface expression of the glutamate transporter excitatory amino acid carrier 1 (EAAC1), thereby inhibiting glutamate uptake and potentially contributing to seizure susceptibility (91). In addition, regulation of ion channels has been implicated in epilepsy pathophysiology. Benign familial neonatal epilepsy (BFNE) is commonly caused by mutations in voltage-gated potassium channels (KCNQ2 and KCNQ3). Soldovieri et al (92) were the first to identify dysfunctional STX1A-channel interactions in BFNE, where mutant STX1A fails to regulate potassium channel activity. Consequently, mutations in these channels reduce M-type K⁺ currents, leading to neuronal hyperexcitability. STX1A binding to K⁺ channels affects these M-currents (93) and STX1A dysfunction may exacerbate the effect. Another study suggested that STX1A-related epileptic encephalopathy is not only characterized by STX1A dysfunction but may also manifest as dysfunction of its binding partner STXBP1 (encoding Munc-18) (94). This indicates that the epileptic phenotype may result from the destruction of a broader presynaptic release network rather than from the action of STX1A alone. This is consistent with the ‘SNAREopathies’ pathological mechanism, emphasizing co-aggregation impairment of presynaptic secretory pathways as a common pathogenic mechanism in epilepsy and neurodevelopmental disorders.

Migraine is a common neurovascular disorder characterized by recurrent headaches, often accompanied by sensory disturbances such as photophobia and phonophobia (95,96). Its global prevalence is higher in females than in males, reflecting contributions from hormonal, genetic, and neurobiological factors. From a genetic standpoint, migraine exhibits a typical complex polygenic architecture, as supported by additional transcriptomic and functional analyses. For instance, a large-scale GWAS identified 123 susceptibility loci and mapped STX1A to one of the implicated regions (97). This finding was further confirmed in studies by Felício et al (98,99). Furthermore, research by Quintas et al (62) indicates that the STX1A gene is associated with migraine susceptibility and is an essential candidate gene for migraines (100). This result has also been confirmed in case-control studies conducted in Portugal (62) and Spain (61). These findings suggest a strong genetic association between STX1A and migraine, but mechanistic investigations into how STX1A variants contribute to migraine pathophysiology remain scarce.

The leading pathophysiological hypotheses of migraine involve cortical spreading depression (CSD), dysfunction of serotonergic and glutamatergic neurotransmission, and neurogenic inflammation (101-103). Recent research has also emphasized the critical role of neurotransmitter systems in migraine pathogenesis (1). In particular, the serotonergic system plays a key role in pain modulation. Consequently, reduced serotonin levels can exacerbate CSD and contribute to the onset of migraine attacks. Clinically, triptans, selective 5-HT₁B/₁D receptor agonists, have proven highly effective in treating migraine (104,105), supporting the central role of serotonin. Therefore, STX1A mutations that reduce serotonin release may represent a potential mechanism for migraine development.

In parallel, glutamate and its receptors have also been implicated in migraine in both pediatric and adult populations (106,107). Epidemiological studies indicate a high comorbidity between migraine and epilepsy. This is especially true in women, individuals with temporal lobe epilepsy, or those who experienced seizures within three months of a migraine diagnosis (108,109). These findings suggest a shared excitatory pathophysiology between the two disorders (110), potentially involving STX1A-mediated regulation of glutamatergic transmission. Excessive glutamate release can also activate N-methyl-D-aspartate receptors and trigger CSD, a neurobiological substrate of migraine aura, thereby promoting trigeminovascular activation and central sensitization, which ultimately culminate in headache (107). It is hypothesized that STX1A modulates excitatory neurotransmission, thereby participating in the pathogenesis of both epilepsy and migraine. Given its involvement in regulating excitatory neurotransmitter release, STX1A could serve not only as a genetic risk factor but also as a potential therapeutic target in migraine. Moreover, its polymorphisms may function as disease-specific biomarkers (100).

AD is the most common form of neurodegenerative disorders, characterized primarily by progressive memory loss and cognitive decline (111). Its hallmark pathological features include extracellular accumulation of β-amyloid (Aβ) forming neuritic plaques and intracellular neurofibrillary tangles composed of hyperphosphorylated tau protein. According to previous studies, synaptic dysfunction and loss of synaptic plasticity are the fundamental pathological processes in the early stages of a variety of neurodegenerative diseases (112-114). STX1A, as a necessary presynaptic t-SNARE protein, is crucial for the secretion of synaptic vesicles. At the protein and transcriptional levels, STX1A is commonly associated with AD. Proteomic analysis of the prefrontal cortex in patients with AD revealed significantly reduced STX1A levels compared with healthy controls (115). A previous large-scale targeted proteomic study has further revealed that the level of STX1A in patients with AD is positively correlated with cognitive function. By contrast, a negative correlation was found with AD pathological burden. In cognitively impaired individuals, the reduction in STX1A may be more pronounced than that in STX1B (116). Collectively, these findings provide strong evidence linking STX1A loss to AD-related cognitive vulnerability. Complementary transcriptomic data further support the concept that synaptic release pathways are disrupted in AD. Significant downregulation of STX1A gene expression was observed in the brains of an AD mouse model and Dp16 mice, which may be a decisive factor in AD-related cognitive decline (117). In addition, emerging cerebrospinal fluid proteomic studies in genetically AD cohorts suggest that proteins involved in synaptic and vesicle cycling pathways exhibit alterations early in the disease course (118). Moreover, Aβ oligomers (a neurotoxic agent) are primary contributors to the pathological process of AD, with the capability of damaging neurons through a variety of mechanisms. Experimental research has also demonstrated that Aβ oligomers directly bind to the SNARE motif of STX1A, thereby inhibiting SNARE complex formation and blocking exocytosis (63). This disruption of synaptic transmission is proposed as an additional potential mechanism by which STX1A contributes to cognitive deficits in AD. However, given the essential and widespread role of STX1A in neurotransmission, directly targeting STX1A carries potential safety concerns, as it could broadly disrupt synaptic release across neurons. Thus, therapeutic strategies may be better directed toward selectively blocking pathological Aβ-STX1A interactions, thereby restoring SNARE-mediated exocytosis and delaying or reversing cognitive decline in AD while minimizing adverse effects. Current therapeutic approaches for AD remain limited in efficacy; therefore, elucidating the role of STX1A could offer new avenues for treatment development.

PD is a chronic neurodegenerative disease characterized by progressive movement disorders. The basic pathological features of PD are the misfolding and abnormal aggregation of α-synuclein (α-Syn) and the loss of dopaminergic neurons in the substantia nigra. Notably, the SNARE complex is also involved in PD pathogenesis (13). Xiong et al (119) observed downregulated STX1A expression in a PD rat model, suggesting that impaired presynaptic release capacity may accompany dopaminergic disorder. Furthermore, patients with PD exhibited elevated α-Syn levels in serum exosomes along with higher clinical scores compared with healthy controls (120). Notably, Agliardi et al (121) also identified a negative correlation between α-Syn and STX1A levels in the serum exosomes of patients with PD. Therefore, these studies suggest an inverse relationship between α-Syn burden and presynaptic STX1A integrity. Collectively, STX1A may serve as a biomarker of presynaptic vulnerability in PD diagnosis.

IS is the most prevalent type of stroke and ranks as the third leading cause of death and disability worldwide. Previous research has reported significant upregulation of STX1A protein levels in the brains of IS rat models, including elevated expression in blood samples from patients with IS (122). These findings suggest that STX1A may serve as a potential clinical biomarker for stroke prognosis. Additionally, elevated levels of γ-aminobutyric acid (GABA) during the subacute phase of IS activate extra-synaptic GABA receptors, leading to tonic inhibition that suppresses post-stroke neuronal excitability and hinders recovery (123-125). GABA transporter 1 (GAT-1) plays a vital role in the reuptake of extracellular GABA, enhancing neuronal excitability and facilitating recovery after stroke. Lin et al (15) discovered that IS induces GAT-1-STX1A interaction, leading to GAT-1 dysfunction in the subacute phase. In a mouse model of stroke, administration of ZLQ-3 (a small-molecule inhibitor that disrupts the GAT-1-STX1A interaction) dissociated the GAT-1-STX1A interaction, successfully restored GAT-1 function, and enhanced GABA reuptake. This mechanism not only increased cortical excitability but also strengthened GABAergic synaptic inhibition, ultimately promoting functional recovery post-stroke (15). Thus, STX1A is a novel therapeutic target for enhancing post-stroke neurorehabilitation.

In addition, Kv2.1 (a voltage-gated K⁺ channel) plays a key role in regulating cell excitability and is also vital following IS. Evidence indicates that Kv2.1 can interact with STX1A to promote K⁺ efflux, thereby contributing to central neuronal apoptosis (126). In vitro studies have shown that disrupting the Kv2.1-STX1A interaction significantly reduces K⁺ efflux, exerting neuroprotective effects (45,127). Another study demonstrated that open-conformation STX1A appears to inhibit Kv channel-mediated K⁺ currents (128), suggesting that this mechanism could be leveraged for neuroprotection.

MS is a common autoimmune disease of the nervous system. Its primary manifestation is chronic inflammation that destroys myelin in the white matter of the brain, leading to demyelinating disorders and progressive neurological dysfunction. With advances in research, MS is no longer regarded as a purely white matter demyelinating disease. Gray matter pathology and synaptic dysfunction have also been increasingly recognized (129). Notably, these alterations may contribute to MS-associated cognitive impairment and neuropsychiatric manifestations. A recent study conducted in Turkish populations found a significant association between STX1A gene polymorphisms and increased MS susceptibility (130). By contrast, similar associations were not observed in German or Egyptian populations (131). This discrepancy suggests that STX1A is unlikely to represent a universal, cross-population driver of MS pathogenesis, but may instead function as a modest, context-dependent genetic modifier.