P2X7 Receptor in Rare Diseases: Shared Molecular Mechanisms and Therapeutic Implications

Abstract

Rare diseases (RDs) are individually uncommon but collectively affect a large global population, and the vast majority still lack effective disease-modifying therapies. With advances in genomics and data-sharing platforms, research has increasingly shifted from a single-disease perspective to the search for convergent molecular pathways that might be shared across clinically distinct entities. In this context, the purinergic P2X7 receptor (P2X7R) has emerged as a putative “shared molecular platform” due to its central role in inflammation amplification, cell death and immune regulation. P2X7R is an ATP-gated ion channel with unique structural and functional features: under high extracellular ATP, it not only forms a non-selective cation channel but can also dilate into a “large pore” permeable to macromolecules, thereby triggering Ca²⁺overload, NLRP3 inflammasome assembly, reactive oxygen species (ROS) production and apoptotic/necrotic-like cell death. This review briefly outlines the epidemiology of RDs and the structural–functional characteristics of P2X7R, then systematically summarizes current evidence linking P2X7R to multiple rare diseases, including Charcot–Marie–Tooth disease, Guillain–Barré syndrome, amyotrophic lateral sclerosis, Huntington’s disease, multiple sclerosis, and selected inflammatory and metabolic RDs (CAPS, familial Mediterranean fever, Systemic sclerosis, Dravet syndrome and Gaucher disease). By comparing P2X7R expression and functional alterations, downstream signaling pathways and pharmacological data from animal models across these conditions, we propose that a P2X7R-dependent network centered on a “Ca²⁺–NLRP3–inflammation/cell death axis” may constitute a common pathogenic backbone for diverse RDs. At the same time, disease-specific spatiotemporal expression patterns of P2X7R in central vs peripheral nervous systems and in immune vs target organ cells confer marked context dependence and “double-edged sword” properties. Finally, we discuss opportunities and challenges for P2X7R-targeted strategies, including the impact of disease stage and sex differences on therapeutic efficacy, and key bottlenecks in translating preclinical findings into clinical benefit. A deeper understanding of both shared and disease-specific roles of P2X7R may provide a conceptual framework and therapeutic entry point for precision stratification and multi-target interventions in rare diseases.

Introduction

Rare diseases (RDs) are typically defined by very low prevalence, but the exact numerical thresholds differ substantially across countries and regions. As a result, some conditions are classified as rare in certain populations yet not in others, leading to inconsistencies in epidemiological estimates, health policy and resource allocation.¹ In a systematic analysis of 1109 institutional definitions covering 296 RDs, Richter et al proposed a global threshold of approximately 40–50 per 100,000 inhabitants as a more realistic prevalence cut-off.² More than 6000 distinct RDs have been described, and their combined point prevalence is estimated at 3.5–5.9% of the world population, corresponding to roughly 263–446 million affected individuals.³

Patients with RDs face multiple challenges throughout the diagnostic and therapeutic journey. Clinically, heterogeneous presentations and limited physician experience lead to frequent under-diagnosis, misdiagnosis and substantial diagnostic delay. Therapeutically, only about 5% of RDs currently have approved treatments, and even when disease-specific therapies exist, access is often constrained by high costs and geographic disparities.⁴ Consequently, RDs severely impair patients’ quality of life and impose a considerable burden on healthcare systems and societies.

With the advent of genomic technologies and the establishment of data-sharing platforms such as GeneMatcher, Matchmaker Exchange and MyGene2, the field has moved beyond purely descriptive nosology toward mechanistic dissection and cross-disease comparison.⁵ In parallel with gene discovery, increasing attention has been directed to convergent molecular pathways that might be “reused” across clinically distinct RDs, offering prospects for therapeutic repurposing and platform-based drug development. Among these, the purinergic P2X7 receptor (P2X7R) has attracted particular interest. P2X7R is an ATP-gated ligand-gated cation channel⁶ primarily expressed in immune-related cells such as dendritic cells,⁷ macrophages,⁸ T lymphocytes,⁹ and glial cells.¹⁰ It senses danger signals, such as elevated extracellular ATP levels, and promotes cation influx while perturbing Ca²⁺ homeostasis, thereby triggering ROS production,¹¹ mitochondrial dysfunction,¹² and NLRP3 inflammasome activation. This ultimately facilitates the release of proinflammatory cytokines such as IL-1βand IL-18, leading to inflammatory amplification and tissue damage.^8,13,14 Accumulating evidence suggests that P2X7R is involved not only in the pathological processes of rare diseases but also in cardiovascular disorders¹⁵ such as atherosclerosis and myocardial ischemia-reperfusion injury, in which its activation may contribute to endothelial injury,¹⁶ macrophage foam cell formation,¹⁷ and plaque inflammation.¹⁸ In tumor-associated inflammation, the interaction between P2X7R and ATP may exert both anti-tumor and pro-tumor effects.¹⁹ In neurodegenerative diseases such as Alzheimer’s disease(AD) and Glaucoma,^20,21 P2X7R may also promote microglial activation and exacerbate neuroinflammatory responses. The above evidence suggests that P2X7R is not merely an accompanying inflammatory molecule but may also play a significant pathological regulatory role in various diseases. Previous reviews have also indicated that, in basal ganglia disorders, purinergic receptors (particularly A₂A and P2X7) may form a shared molecular platform linking Huntington’s disease and Parkinson’s disease through disturbances in Ca²⁺ signaling and neuroinflammation.^22–25

Inspired by this concept, the present review focuses on P2X7R in RDs. We summarize the structural and functional properties of P2X7R, then examine its involvement in selected rare neurological, inflammatory and metabolic diseases. We further highlight convergent and divergent P2X7R-mediated pathways across these entities and discuss the emerging potential of P2X7R as a diagnostic, prognostic and therapeutic target within a precision medicine framework for RDs.

Structure, Activation, and Functional Roles of P2X7 Receptors

Structural Features of P2X7R

P2X7 receptor (P2X7R) is an ATP-gated ionotropic member of the P2X receptor (P2XR) family. In mammals, functional P2X7R is primarily assembled as homotrimers and only rarely forms heterotrimers.^6,26–28 The receptor is composed of three subunits, and each P2X7R subunit comprises two transmembrane domains (TM1 and TM2), a large extracellular loop, and intracellular N-terminal and extended C-terminal domains. Each subunit contains 595 (or 594) amino acid residues,⁶ with the extracellular domain (282 amino acids across three subunits) being rich in cysteine and possessing three potential ATP-binding sites. Through extensive intersubunit interactions, the extracellular domain adopts a cup-shaped conformation, and occupancy of at least two binding sites is typically sufficient to activate the receptor.^10,29 Each P2X7R subunit contains two transmembrane helices, TM1 and TM2, each approximately 24 amino acids in length; at the trimeric level, the receptor comprises six α-helices in total, with TM1 positioned peripherally and TM2 lining the central ion-conducting pore.³⁰ The cytoplasmic components include the intracellular N-terminus (26 amino acids) and the extended C-terminus (residues 356–595), collectively referred to as the cytoplasmic cap,³¹ which is implicated in P2X7R gating, desensitization, and large-pore formation. The N-terminus contains a protein kinase C (PKC) phosphorylation consensus sequence, which contributes to receptor gating, conformational regulation, and downstream signaling^32,33 The C-terminus of P2X7R is the longest within the P2X receptor (P2XR) family and represents one of its most distinctive structural features. This domain contains a cysteine-rich cytoplasmic region (also known as the C-cys anchor region, at the C-terminal end of TM2)^32,34 and a cytoplasmic ballast region (an additional ~120 residues at the C-terminus).^35,36 CCryo-electron microscopy studies have shown that C-cys functions as a molecular hinge, with its palmitoyl groups anchoring TM2 to the inner pore lining and the cytoplasmic domain to the inner leaflet of the lipid membrane, thereby helping to preserve receptor activity and delay desensitization, which endows P2X7R with sustained signaling capability.³⁴ Additionally, the unique C-terminal tail is associated with macropore formation and increased plasma membrane permeability.³⁷ Experiments have shown that the C-terminal domain of full-length rat P2X7R undergoes marked conformational rearrangement upon ATP binding, which may promote pore formation. Furthermore, researchers have identified a binuclear zinc-ion complex and a high-affinity guanylate-binding site in the cytoplasmic vestibule, providing new insights into the future functional characterization of P2X7R.^34,38

Activation and Pore Formation of P2X7R

The activation of P2X7R is multifactorially regulated by ligand binding, allosteric modulation, post-translational modifications, and protein-protein interactions.^15,37 Among these factors, high extracellular ATP is the primary endogenous agonist, and ATP sensitivity differs markedly among species. It has been reported that rat P2X7R is the most ATP-sensitive (EC₅₀~0.1–0.3 mM), mouse P2X7R exhibits intermediate sensitivity (EC₅₀~0.7–1.2 mM), and human P2X7R is the least sensitive, with an initial activation EC₅₀>1 mM and, in some buffers, exceeding 2.5 mM.^39–41 The activation potency of the nucleotide analog BzATP is up to 30-fold higher than that of ATP, making it one of the most potent P2X7R agonists. BzATP also exhibits marked species-dependent differences in potency: the EC₅₀ is approximately 7–16 μM in rats, 58–132 μM in mice, and 170–254 μM in humans.³⁹ Divalent cations such as Ca²⁺ and Mg²⁺ can act as allosteric inhibitors that modulate receptor activity,^42–44 whereas compounds such as LL-37,⁴⁵ ivermectin,⁴⁶ ginsenosides,⁴⁷ and LPS^15,48 can increase P2X7R sensitivity to ATP or lower the ATP concentration threshold required for activation. In addition, Panx1-mediated hemichannel opening is also one of the classical signaling pathways associated with P2X7R activation. Panx1 is a plasma membrane hemichannel protein.^49,50 Under pathological conditions, inflammatory stimuli such as LPS,⁵¹ and TNF-α⁵² can promote Panx1 opening by activating caspase-11 in mice or caspase-4/5 in humans, which cleave the C-terminal domain of Panx1, thereby facilitating ATP efflux and establishing a positive feedback loop with P2X7R.^51,53 Conversely, the ionic imbalance induced by P2X7R activation may enhance Panx1 channel activity and increase membrane permeability, thereby exacerbating ATP release and disruption of ionic homeostasis, ultimately creating a permissive environment for inflammasome assembly and activation.^54–56

Under pathological conditions such as tissue damage,⁵⁷ infection, or oxygen-glucose deprivation (OGD),⁵⁸ elevated extracellular ATP levels can activate P2X7R. Upon activation, P2X7R briefly opens a non-selective cation channel, causing Na⁺, Ca²⁺ influx and K⁺ efflux.³⁴ Under sustained ATP stimulation, P2X7R forms a distinctive large pore that permits the passage of hydrophilic molecules with molecular weights of up to approximately 900 Da, thereby increasing plasma membrane permeability to larger solutes.^59–61 This channel not only mediates the uptake of cationic dyes such as YO-PRO-1 and ethidium bromide but also facilitates the cellular entry of anionic dyes, such as Lucifer Yellow and carboxyfluorescein. However, the permeability of large pores to molecules of different charges is influenced by multiple factors. Existing experimental evidence suggests that their selectivity for different molecules may be affected by cell type, experimental temperature, and the involvement of related pathways, such as Cl- and Panx1 channel.^{38,60,62–64}

Physiological and Pathological Roles of P2X7R

P2X7R is involved in a wide range of physiological and pathological processes, including inflammation,¹⁵ pain,^65,66 cell proliferation and differentiation,⁶⁷ as well as the regulation of apoptosis,⁶⁸ pyroptosis,¹⁴ necroptosis,⁶⁹ and autophagy.⁷⁰ In microglia, P2X7R activation induces K⁺ efflux, thereby promoting the assembly of the NLRP3 inflammasome with ASC and pro-caspase-1, leading to caspase-1 activation; Activated caspase-1 also cleaves pro-GSDMD to generate gasdermin D (GSDMD), which forms membrane pores and, in concert with P2X7R-associated signaling pathways, promotes the release of IL-1β and IL-18, ultimately induces pyroptosis.^8,13,71,72 Meanwhile, Ca²⁺ influx and aberrant activation of store-operated calcium entry (SOCE) can lead to ROS accumulation,⁷³ impairment of antioxidant defense, and mitochondrial dysfunction,⁷⁴ thereby inducing cytochrome c release and activation of caspase-3, −8, and −9.^12,75,76 P2X7R can also promote the biogenesis and release⁶⁵ of microglial exosomes through membrane depolarization and cytoskeletal remodeling,^77,78 thereby allowing inflammatory signals to spread to adjacent neurons and glial cells^78,79 P2X7R activation can also promote glutamate release,⁸⁰ induce excitotoxicity, and, in the presence of TNF-α,⁷⁴ trigger necroptotic cell death, thereby exacerbating neuronal injury. Outside the central nervous system, in antigen-presenting cells⁸¹ such as macrophages and dendritic cells, P2X7R activation promotes cell maturation and upregulates MHC class I/II and co-stimulatory molecules such as CD80/CD86,⁸² thereby enhancing antigen-presenting capacity and inflammasome-associated IL-1βand IL-18 production. This in turn drives the polarization of naive CD4⁺T cells toward Th1/Th17 effector phenotypes and influences CD8⁺T-cell activation, Treg-to-Th17 transdifferentiation, and Tfh-cell survival.^83,84 On the other hand, P2X7R can also enhance APC cross-dressing by promoting plasma membrane remodeling and exosome-mediated transfer of antigen-MHC complexes, thereby amplifying direct antigen presentation and indirect antigen recognition pathways. This process is particularly important in contexts such as viral infection, antitumor immunity, and transplant rejection.^7,9,85,86

The structural features, activation mechanisms, and major downstream signaling pathways of P2X7R are summarized in Figure 1. As our understanding of P2X7R structure, physiology and disease involvement has grown, this receptor has evolved from being viewed merely as an “inflammatory channel” to a promising therapeutic target in multiple conditions. The following sections synthesize current evidence on P2X7R-mediated mechanisms in specific RDs and attempt to distill cross-disease commonalities.

Figure 1.

Structural features, activation mechanisms, and major downstream signaling pathways of the P2X7R.

Notes: Top middle (P2X7R structure): P2X7R is an ATP-gated cation channel composed of two transmembrane domains (TM1 and TM2), a cysteine-rich extracellular domain, an intracellular N-terminal region, and a uniquely C-terminal tail.//Left to right (activation mechanisms and signaling pathways): Inflammatory stimuli activate the TLR4/NF-κB signaling pathway, thereby inducing the transcriptional upregulation of NLRP3, pro-IL-1β, and pro-IL-18. Extracellular ATP activates P2X7R, triggering Na⁺ and Ca²⁺ influx, K⁺ efflux, and a transition of the receptor to a large pore state. P2X7R activation further promotes pannexin-1 (Panx1)-mediated ATP release, NLRP3 inflammasome assembly, caspase-1 activation, gasdermin D (GSDMD) cleavage, and the secretion of IL-1β and IL-18, ultimately leading to inflammatory cell death. Meanwhile, reactive oxygen species (ROS) production and mitochondrial dysfunction activate apoptotic pathways via caspase-3/8/9 signaling.//Upper right and lower right (physiological and pathological functions of P2X7R): P2X7R activation also induces glutamate release, neuronal injury, exosome secretion, antigen-presenting cell (APC) phenotypic modulation, and Th1/Th17 polarization. In summary, P2X7R plays a pivotal regulatory role in inflammation, neurodegenerative processes, and immune responses. Overall, P2X7R integrates ionic homeostasis disturbance, inflammasome activation, cell death pathways, and immune regulation, thereby contributing critically to the pathogenesis of neurological, immune-related, and various rare diseases.

P2X7 Receptors and Rare Diseases

Charcot–Marie–Tooth Disease and P2X7R

Charcot–Marie–Tooth disease (CMT) comprises a group of highly heterogeneous hereditary peripheral neuropathies characterized by distal muscle weakness and atrophy, sensory loss, and reduced tendon reflexes. The most prevalent subtype, CMT1A, accounts for approximately 50% of CMT cases and is caused by duplication of the PMP22 gene, leading to Schwann cell dysfunction and myelin instability, and ultimately to demyelinating pathology.^87,88 A recent review by Dong et al comprehensively summarized the current therapeutic landscape for CMT, covering pharmacological, gene-based, and cell-based strategies. Notably, the authors pointed out that while most therapies that have reached clinical trials are drug-based, gene-based approaches—aside from CMT2S—have yet to reach the clinical stage, highlighting the substantial translational barriers that continue to limit progress in this field.⁸⁹ Despite these efforts, no disease-modifying therapy has yet been approved, and current management remains largely supportive, relying mainly on symptomatic pharmacotherapy, orthopedic interventions, and rehabilitation.⁹⁰

Available experimental evidence suggests that P2X7R may contribute to CMT1A pathogenesis. In a CMT1A rat model, PMP22 overexpression was associated with P2X7R upregulation and increased P2X7R-mediated intracellular Ca²⁺ levels in Schwann cells, which were linked to impaired myelinating capacity.⁹¹ In the same experimental context, the selective P2X7R antagonist A438079 was well tolerated and was reported to improve molecular abnormalities, nerve conduction, and myelin structure.⁹² Similarly, the diadenosine 5′,5′′′-P1,P2-diphosphate (Ap2A) isomer P18, which acts as a P2X7R antagonist and P2Y11 receptor agonist, reduced non-phosphorylated neurofilament levels and enhanced Schwann cell myelination in CMT1A dorsal root ganglion co-cultures.⁹³ However, these findings are derived mainly from preclinical models, and their relevance to human disease remains to be established. More broadly, P2X7R has been implicated in neurological and inflammatory disorders characterized by glial dysfunction, axonal injury, and neuroinflammatory responses, as reviewed by Burnstock and Knight.⁹⁴ This broader body of literature provides mechanistic context for considering P2X7R as a candidate target worthy of further investigation in peripheral neuropathies, including CMT1A.

An ideal therapeutic strategy for CMT1A would be to directly reduce Schwann cell PMP22 expression; however, multiple approaches aimed at downregulating PMP22 have not yet translated into effective therapies in humans.⁹⁵ In this context, pharmacological blockade of P2X7R may represent a complementary preclinical strategy to limit Ca²⁺ overload and inflammatory signaling and thereby improve Schwann cell function. Further studies are needed to define the role of P2X7R-centered signaling networks in CMT1A and to determine whether these preclinical observations can be translated into clinically meaningful benefits.

Guillain–Barré Syndrome and P2X7R

Guillain–Barré syndrome (GBS) is an acute immune-mediated polyradiculoneuropathy and a leading cause of acute flaccid paralysis. Its clinical presentation is heterogeneous, but typically includes rapidly progressive limb weakness, sensory disturbances and decreased or absent deep tendon reflexes; severe cases may develop respiratory failure. First-line therapies consist of intravenous immunoglobulin (IVIg), plasma exchange and corticosteroids, yet approximately 20% of patients remain severely disabled and about 5% die despite immunotherapy.^96,97

The precise pathogenesis of GBS remains incompletely understood. Epidemiological data indicate that many cases are preceded by infection, including viral infections such as COVID-19, and major infectious disease outbreaks have been associated with increased GBS incidence.⁹⁸ Simões et al proposed that excessive ATP release and subsequent purinergic signaling following viral infection may be a crucial mechanistic link between infection and GBS onset, with P2X7R—especially when targeted by antagonists with favorable blood–brain barrier penetration and bioavailability—representing an attractive therapeutic candidate.⁹⁹

Xie et al reported significantly elevated P2X7R expression in peripheral blood mononuclear cells from GBS patients and in experimental autoimmune neuritis (EAN), the classical animal model of GBS. Treatment with the P2X7R antagonist Brilliant Blue G (BBG) attenuated clinical manifestations in EAN rats by modulating NLRP3 inflammasome activation and Th1/Th17 differentiation.¹⁰⁰ These findings suggest that P2X7R promotes aberrant inflammation and immune imbalance in GBS and may be a promising target for intervention.

Further studies are warranted to quantify the relationship between P2X7R expression, disease severity and long-term outcome, and to assess whether P2X7R involvement differs among GBS subtypes (eg AIDP vs AMAN), which would be crucial for subtype-specific and individualized therapeutic strategies.

Amyotrophic Lateral Sclerosis and P2X7R

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder characterized by the degeneration of upper and lower motor neurons, leading to muscle weakness, atrophy, spasticity and paralysis, with respiratory failure being the main cause of death. Approximately 10% of cases are familial ALS (FALS), while the remainder are sporadic ALS (SALS).^101,102 Despite intensive research, ALS remains incurable, and current treatments offer only modest survival benefits.

P2X7R has been implicated in several ALS-related pathological processes, including neuroinflammation, glial activation, excitotoxicity and autophagy dysregulation. Post-mortem studies have demonstrated increased P2X7R immunoreactivity in microglia/macrophages in the spinal cord of ALS patients.¹⁰³ In SOD1G93A mice, a widely used ALS model, Gandelman et al showed that a neurotoxic astrocyte phenotype is dependent on basal P2X7R activation. Under pathological conditions, astrocytes sense high extracellular ATP and activate P2X7R, leading to ROS production and the release of pro-inflammatory cytokines such as IL-6, which exacerbate neuroinflammation and motor neuron injury.¹⁰⁴

In the same model, P2X7R activation markedly enhances NADPH oxidase 2 (NOX2) activity in microglia, driving ROS generation and neurotoxicity; these deleterious effects are reversed by genetic ablation or pharmacological inhibition of P2X7R.^105,106 P2X7R activation is also linked to autophagy modulation: in SOD1G93A microglia, P2X7R stimulation increases the autophagy marker LC3-II in an mTOR-dependent manner and upregulates M2-like markers. Short-term stimulation decreases SQSTM1/p62, consistent with autophagy activation, whereas prolonged stimulation increases SQSTM1/p62, indicative of impaired autophagic flux; these changes are prevented by the P2X7R antagonist A-804598 and the autophagy inhibitor wortmannin.¹⁰⁷ Treatment with the novel P2X7R antagonist AXX71 further demonstrated that dampening neuroinflammation and restoring autophagy can improve disease course when administered at early symptomatic stages.¹⁰⁸

However, not all data support a purely detrimental role of P2X7R in ALS. Reduced P2X7R expression has been reported in peripheral blood mononuclear cells from ALS patients, associated with disturbed intracellular Ca²⁺homeostasis.¹⁰⁹ In SOD1G93A mice, the selective P2X7 agonist BzATP exhibits protective effects on skeletal muscle by improving neuromuscular junction innervation and metabolism, and promoting satellite cell proliferation and differentiation, thereby attenuating denervation-induced atrophy.¹¹⁰ Savina Apolloni et al showed that global P2X7R knockout in SOD1G93A mice aggravates disease progression, increasing motor neuron loss and gliosis and accelerating clinical decline. Interestingly, P2X7R deficiency extended lifespan by 6–7% in female but not male SOD1G93Amice, indicating sex-dependent effects.¹¹¹ Consistently, the P2X7R antagonist JNJ-47965567, when administered from the pre-symptomatic phase, delayed disease progression in female but not male SOD1G93A mice,¹¹² although a subsequent study with a different dosing schedule failed to replicate these benefits.¹¹³ BBG administration further revealed that initiating treatment at late pre-symptomatic stages (around day 100) confers neuroprotective effects, whereas treatment at very early pre-symptomatic stages yields limited benefit.¹¹⁴

Taken together, these findings highlight a pronounced “double-edged sword” nature of P2X7R in ALS: on the one hand, it promotes neuroinflammation and neurotoxicity; on the other, it may support protective processes in skeletal muscle and certain glial phenotypes. Rational design of P2X7R-targeted strategies in ALS must therefore consider: (i) cell- and tissue-specific roles; (ii) disease stage and therapeutic window; (iii) dose–response relationships and treatment schedules; and (iv) sex-dependent effects. Conditional knockout models and temporally controlled interventions will be crucial to enable multi-target regimens that protect both motor neurons and skeletal muscle.

Huntington’s Disease and P2X7R

Huntington’s disease (HD) is a rare autosomal dominant neurodegenerative disorder caused by CAG trinucleotide expansion in the HTT gene, leading to the production of mutant huntingtin (mHTT). Pathologically, HD is characterized by progressive degeneration of striatal and cortical neurons, and clinically by motor disturbances, cognitive decline and psychiatric symptoms. Current therapies are largely symptomatic, and no disease-modifying treatment has been unequivocally established.^115,116 Therapeutic efforts are focused on lowering mHTT levels, but challenges in delivery, safety and long-term efficacy remain, underscoring the need for adjunctive neuroprotective and anti-inflammatory strategies.

Several studies have documented altered P2X7R expression and function in HD. In two different HD mouse models, striatal P2X7R levels are markedly increased, and mHTT-expressing cultured neurons exhibit heightened susceptibility to P2X7R agonist-induced apoptosis. P2X7R antagonism with BBG significantly improves motor coordination and body weight and delays disease progression in HD mice.¹¹⁷ In ex vivo models, HD-associated P2X7R upregulation reshapes receptor signaling, and BzATP induces cell death and impairs synaptic transmission, effects reversed by the antagonist OxATP.²⁴

More recently, human post-mortem studies have shown upregulation of both full-length P2X7R (P2X7R-A) and a naturally occurring C-terminal-truncated variant (P2X7R-B) in the striatum of HD patients. Beyond increased overall mRNA, splicing patterns are altered, with slightly reduced exon 4 inclusion and significantly increased intron 10–11 retention.¹¹⁸ These findings reinforce a role for P2X7R in HD pathogenesis and raise the possibility that distinct P2X7R splice variants mediate specific pathological effects.

Future research priorities in HD include: (i) dissecting the interplay between P2X7R and core pathogenic mechanisms such as mHTT aggregation, oxidative stress and mitochondrial dysfunction; (ii) evaluating combination approaches that pair P2X7R antagonists with mHTT-lowering agents (eg antisense oligonucleotides, small-molecule degraders), aiming at “causal plus protective” interventions; and (iii) investigating the impact of P2RX7 polymorphisms on HD susceptibility and treatment response to enable personalized P2X7R-based strategies.

Multiple Sclerosis and P2X7R

Multiple sclerosis (MS) is a chronic autoimmune inflammatory disease of the central nervous system characterized pathologically by multifocal demyelination, inflammatory infiltrates and gliosis. Over time, axonal damage and loss accumulate, leading to irreversible neurodegeneration. Clinically, MS manifests as disseminated neurological deficits in space and time, with highly heterogeneous courses ranging from relapsing–remitting to progressive phenotypes. Although a broad array of disease-modifying therapies is now available, no single intervention fully addresses the complex immunoinflammatory and neurodegenerative components of MS.^119,120

Purinergic signaling has emerged as a relevant pathway in MS pathophysiology, with P2X7R being a particularly promising target due to its role in inflammasome activation and neurodegeneration. Post-mortem analyses have demonstrated elevated P2X7R expression in activated microglia and astrocytes within spinal cord and brain lesions of MS patients.^103,121 In progressive MS, increased P2X7R levels have also been reported in frontal cortical astrocytes.¹²² Matute et al observed P2X7R upregulation in apparently normal-appearing fiber tracts, where enhanced ATP signaling was associated with excitotoxic damage and death of oligodendrocytes, suggesting that P2X7R-mediated changes may precede overt lesion formation.¹²³ Collectively, these observations support the hypothesis that P2X7R antagonists may exert protective effects by attenuating glial-mediated injury and demyelination.

In experimental autoimmune encephalomyelitis (EAE), P2X7R protein levels increase before clinical onset, initially in astrocytes, and further rise at the mRNA and protein levels as disease progresses, with higher expression also observed in neurons.¹²⁴ Early astrocyte and microglial activation precede overt neurological deficits. BBG, a commonly used P2X7R antagonist with limited selectivity, significantly reduces astrogliosis and microgliosis and delays or attenuates clinical signs in EAE animals.^125,126 It should be noted that some P2X7R antagonists do not exhibit absolute specificity (see Table 1 for details on the specificity, mechanisms of action, disease applications, and developmental stages of the relevant P2X7R antagonists discussed in the text). Another P2X7R antagonist not only ameliorates EAE severity but also upregulates the blood–brain barrier–related proteins claudin-5 and PDGFβR, suggesting that P2X7R blockade can help preserve barrier integrity.¹²⁷ Genetic deletion studies demonstrated that P2X7R-deficient mice show a roughly four-fold reduction in EAE incidence, with diminished astrogliosis and axonal damage compared with wild-type controls.¹²⁸ In the T cell-independent cuprizone demyelination model, P2X7R knockout reduces M1-like microglial polarization and astrogliosis, resulting in less demyelination and lower expression of inflammatory genes.¹²⁹

Table 1.

Comprehensive Overview of P2X7R Antagonists: Selectivity, Mechanism, CNS Penetration, Development Stage, and Disease Relevance

P2X7R Antagonists	Selectivity	Mechanism	CNS Penetration	Effect on Panx1	IC50 Values of P2X7R(μM)* 130–134	Known off-Target Effects	Rare Disease Indications	Development Stage	Major Pathological Effects	Refs
					Human [h], Rat [r], or Mouse [m]
OxATP	Poor	Irreversible antagonist	Poor	No evidence available	173–285(h) ≈ 100(m)	Irreversibly modifies extracellular proteins and may affect multiple purinergic signaling pathways	MS,HD	Experimental research tool compound	NF-κB signaling ↓; Cytokine release ↓	[135–138]
BBG	Moderate	Non-competitive	Limited	Direct Panx1 inhibition	0.010–0.013(r) 0.27(h)	Inhibits Panx1 channels, voltage-gated sodium channels, and P2X4 receptors at higher concentrations	ALS,HD,MS,GBS,AD	Preclinical proof-of-concept antagonist	Neuroinflammation ↓; Microglial activation ↓; Excitotoxicity ↓; Motor neuron protection ↑	[75,139–147]
A-740003	High	Competitive antagonist	Limited	Indirect effect on Panx1-associated signaling	0.04 (h) 0.02 (r)	Minimal reported off-target activity (IC50 >10 μM at other tested receptors, ion channels, transporters and enzymes)	ALS,HD,MS	Preclinical pharmacological tool compound	Attenuation of neuroinflammation, IL-1β cascade, and neuropathic/inflammatory pain.	[139,142,148–151]
A-438079	High	Competitive antagonist	Limited	Indirect effect on Panx1-associated signaling	0.13 (h) 0.32 (r) 2.90 (m)	No major off-target activity reported; highly selective P2X7R antagonist	MS,HD,CMT	Preclinical pharmacological tool compound	Neuroinflammation ↓; IL-1β signaling ↓	[152–157]
JNJ-47965567	Very high	Allosteric antagonist	Good	No direct evidence available	0.005–0.035 (h) 0.0047–0.098 (r) 0.00065 (m)	Weak off-target activity at SERT, MT1 receptor, and CYP1A2 at micromolar concentrations	HD,MS,ALS*(Mixed preclinical evidence)	Translational preclinical candidate	Neuroinflammation ↓; Motor neuron protection ↑	[38,39,158,159]
JNJ-55308942	Very high	Allosteric antagonist	Good	No direct evidence available	0.010 (h) 0.015 (r)	High selectivity; potential off-target effects at high concentrations	AD,HD	Advanced preclinical candidate	IL-1β release ↓; Microglial activation ↓; Anhedonia-like behavioral deficits ↓	[160–162]
JNJ-54175446	Very high	Allosteric antagonist	Good	No direct evidence available	0.003 (h)	High selectivity; potential off-target effects at high concentrations	AD	Clinical-stage P2X7R antagonist (Phase II evaluation)	IL-1β signaling ↓; Neuroinflammation ↓; Mood-related behavioral deficits ↓	[75,162–165]

Notes: *1. ↓ indicates reduction, inhibition, or attenuation; ↑ indicates increase, enhancement, or protection. *2. The IC₅₀ values listed in the table are provided for reference only, as antagonist potency may vary substantially depending on the agonist used and the extracellular milieu. For example, the P2X7R inhibitory activities of oxATP and BBG may differ by 10 to 20 fold.¹⁶⁶

Abbreviations: BBG, Brilliant blue G; CNS, central nervous system; Panx1, Pannexin-1; AD, Alzheimer’s disease; ALS, Amyotrophic Lateral Sclerosis; GBS, Guillain-Barré syndrome; HD, Huntington’s disease; MS, Multiple Sclerosis; PD, Parkinson’s disease; CMT, Charcot-Marie-Tooth disease.

In contrast, Brosnan et al reported more severe EAE in P2X7R−/− mice, which was attributed to impaired apoptosis of autoimmune lymphocytes, leading to their persistence and aggravated autoimmune responses.¹⁶⁷ However, it should also be considered that P2X7R deficiency may reduce ATP-induced apoptosis of regulatory T cells, which could favor their survival and alter immune homeostasis.¹⁶⁸ These findings highlight a potential risk of systemic P2X7R inhibition: while it may attenuate CNS inflammation and demyelination, it could simultaneously disrupt physiological immune homeostasis by affecting both pathogenic and regulatory lymphocyte populations.

Genetic studies have further linked P2RX7 variants to MS risk and severity. Oyanguren-Desez et al found that the T allele of rs17525809, which results in an Ala-76-to-Val substitution, is more frequent in MS patients and confers a gain-of-function phenotype characterized by increased Ca²⁺ influx, enhanced electrophysiological responses, and higher ethidium uptake.¹⁶⁹ Guerini et al genotyped 189 healthy controls and 128 MS patients (94 relapsing–remitting, 34 secondary progressive) and assessed disease severity using the Multiple Sclerosis Severity Score (MSSS). Two P2RX7 SNPs (rs1718119, Ala348Thr; rs2230912, Gln464Arg) were significantly associated with higher MSSS in relapsing–remitting MS, and both minor alleles are known gain-of-function variants.¹⁷⁰

Overall, P2X7R in MS fulfills dual and partly opposing roles: in CNS glia, its activation promotes inflammation and demyelination, whereas in peripheral immune cells it participates in the apoptotic clearance of harmful autoreactive lymphocytes. Clinically, a rational approach might involve preferential targeting of CNS P2X7R while preserving or even supporting beneficial peripheral immune functions. Integrating P2RX7 genotyping into patient stratification could further optimize candidate selection and dosing for P2X7R-modulating therapies.

Taken together, the evidence presented above suggests that P2X7R may contribute to the pathogenesis of these five neurological rare diseases through dysregulated calcium signaling, exacerbated inflammatory responses, glial activation, neuronal damage, myelin abnormalities, and blood-brain barrier disruption, as shown in Figure 2.

Figure 2.

This schematic highlights the critical roles of the P2X7 receptor (P2X7R) in rare diseases.

Notes: Upper left (CMT): PMP22 overexpression upregulates P2X7R, causing increased intracellular Ca²⁺ and Schwann cell dysfunction, leading to myelination defects in CMT1A.//Lower left (ALS): Extracellular ATP activates P2X7R in glial cells, driving ROS production and IL-6 release, which exacerbate neuroinflammation and motor neuron injury. P2X7R enhances NOX2 activity and modulates autophagy via mTOR and SQSTM1/p62 pathways.//Bottom (HD): P2X7R is elevated in HD models, where its activation induces neuronal death and synaptic impairment. Both full-length (P2X7R-A) and truncated (P2X7R-B) forms increase in patient striatum.//Upper right (GBS): P2X7R levels rise in GBS and EAN models; antagonism with Brilliant Blue G reduces symptoms by inhibiting inflammasome activation and Th1/Th17 polarization.//Right (MS): P2X7R in glial cells mediates ATP-driven excitotoxicity, disrupts BBB via claudin-5 and PDGFβR regulation. The rs17525809 variant alters calcium permeability, resulting in heightened electrophysiological responses and elevated ethidium uptake. ↑ indicates enhanced function or upregulated P2X7R levels. In summary, P2X7R-mediated calcium signaling and immuno-inflammatory responses play central roles in the pathogenesis of various rare diseases, highlighting its importance as a potential therapeutic target.

Abbreviations: ALS, amyotrophic lateral sclerosis; BBB, blood-brain barrier; CMT, Charcot-Marie-Tooth disease; EAN, experimental autoimmune neuritis; GBS, Guillain-Barré syndrome; HD, Huntington’s disease; IL-6, interleukin-6; MS, multiple sclerosis; NOX2, NADPH oxidase 2; ROS, reactive oxygen species; Th, T helper.

Other Rare Diseases and P2X7R

Beyond the neurological RDs described above, P2X7R may indirectly contribute to the pathogenesis or treatment response of several rare inflammatory and metabolic disorders by modulating inflammasome activation, neuronal excitability or lysosomal function.

Cryopyrin-associated periodic syndrome (CAPS) comprises a group of autoinflammatory conditions caused by NLRP3 mutations, leading to constitutive inflammasome activation and excessive IL-1β release, which in turn drives systemic inflammation.¹⁷¹ Although direct evidence for an essential role of P2X7R in CAPS pathogenesis is lacking, its established function as an upstream trigger of NLRP3 inflammasomes suggests that P2X7R antagonists could dampen IL-1β production and alleviate symptoms, particularly in cases with suboptimal response to IL-1 inhibitors such as anakinra.

Familial Mediterranean fever (FMF) is an autosomal recessive periodic fever syndrome characterized by recurrent episodes of fever and serositis, most often caused by mutations in MEFV, the Mediterranean fever gene, which encodes pyrin and leads to enhanced inflammasome activity and IL-1β secretion.^172,173 Colchicine is the first-line therapy. Recent studies indicate that one of colchicine’s key mechanisms may be the inhibition of P2X7R-mediated pore formation, thereby indirectly suppressing inflammasome activation and IL-1β release.¹⁷⁴ Because P2X7R activation can promote K⁺ efflux and downstream inflammasome signaling, it may also engage pathways that converge on gasdermin D-dependent membrane pore formation and pyroptotic cytokine release.^175,176 However, whether colchicine directly affects gasdermin D remains unclear. Taken together, these findings suggest that P2X7R may modulate FMF disease activity and treatment response through pathways linked to inflammasome activation and pyroptosis.

Systemic sclerosis (SSc) is a multifaceted immune-mediated connective tissue disease characterized by immune dysregulation, vasculopathy, and progressive fibrosis involving the skin and multiple internal organs. Although therapeutic strategies have improved in recent years, current management remains largely organ-directed and symptomatic, with limited capacity to directly suppress the underlying fibrotic process.^177,178 In this context, the purinergic P2X7 receptor (P2X7R) has been reported to be associated with SSc-related inflammatory and fibrotic responses. Notably, studies in dermal fibroblasts derived from patients with SSc have shown that P2X7R is markedly upregulated and that its activation promotes calcium influx and a profibrotic phenotype, characterized by increased α-SMA expression, enhanced cell migration, and elevated collagen and CTGF production. Inhibition of the ERK pathway has been shown to abolish the pro-collagen effect of P2X7R activation, suggesting that ERK signaling may serve as a key downstream mediator.¹⁷⁹ Therefore, P2X7R may represent a potential therapeutic target in SSc; however, these findings were obtained in vitro (often under LPS‑primed conditions) and in studies with relatively small sample sizes, and thus require confirmation in larger cohorts and in vivo models before translational conclusions can be drawn.

Dravet syndrome (DS) is a rare, severe, drug-resistant epileptic encephalopathy with onset in infancy, classified as a developmental and epileptic encephalopathy (DEE). Approximately 80% of patients harbor SCN1A mutations.¹⁸⁰ Clinically, DS is characterized by multiple seizure types, intellectual disability and motor delays. Therapeutic goals focus on seizure reduction and quality-of-life improvement. P2X7R contributes to epileptogenesis via mechanisms including cell death, synaptic plasticity changes, blood–brain barrier disruption and neurotransmitter release. In animal models, P2X7R antagonists have shown anti-seizure effects.^181,182 Although a direct causal link between P2X7R and DS has not been established, the receptor’s roles in neuroinflammation, excitability and neuroprotection make it a plausible adjunct target. Genetically precise models could be used to assess the impact of P2X7R modulation on seizure control and developmental outcomes.

Gaucher disease (GD) is an autosomal recessive lysosomal storage disorder caused by GBA1 mutations leading to deficient β-glucocerebrosidase (GCase) activity and accumulation of glucocerebroside in macrophages (“Gaucher cells”), with multi-organ involvement and, in some subtypes, central nervous system degeneration.¹⁸³ Enzyme replacement therapy effectively improves many systemic manifestations of type I GD, but therapeutic options for neuronopathic forms remain limited. In addition to its well-established role in inflammation, P2X7R has been reported to modulate membrane trafficking processes, including phagosome maturation and fusion with lysosomes, exocytosis of secretory lysosomes, and the release of microvesicles and exosomes.¹⁸⁴ P2X7R also contributes to membrane lipid homeostasis and asymmetry by promoting phosphatidylserine externalization and loss of phospholipid asymmetry, thereby affecting membrane stability and endomembrane organization.¹⁸⁴ P2X7R has also been implicated in the regulation of lipophagy through the AMPK/ULK1 pathway, thereby influencing intracellular lipid accumulation and lysosomal dynamics.¹⁸⁵ Given that GD is characterized by glucocerebroside accumulation in macrophages, P2X7R-mediated modulation of lysosomal fusion, membrane lipid homeostasis, and lipophagy may represent additional mechanisms by which this receptor could influence disease progression. These observations further support P2X7R as a potential therapeutic target in GD, particularly for modulating lysosomal function and lipid metabolism beyond its established roles in inflammation.

Overall, current studies only suggest that P2X7R may be involved in the inflammatory regulation, altered neuronal excitability, or lysosomal and autophagic dysfunction in certain rare inflammatory or metabolic diseases. However, most of the available evidence comes from indirect mechanistic inference or preclinical studies, and the strength of evidence varies across conditions. Therefore, P2X7R is currently better considered a candidate mechanism that may contribute to the pathogenesis of selected rare diseases and warrants further validation.

Shared Molecular Mechanisms of P2X7R Across Rare Diseases

Despite striking differences in genetic etiology, target organs and clinical phenotypes, the RDs discussed above appear to converge on several P2X7R-centered mechanisms:

Ca²⁺ Overload and Mitochondrial Dysfunction as a Central Hub

In CMT1A Schwann cells, peripheral nerves in GBS, CNS tissue in ALS/HD/MS and macrophages in GD, excessive P2X7R activation induces Ca²⁺ influx, mitochondrial depolarization, ROS generation and engagement of cell death cascades. The Ca²⁺–mitochondrial axis thus serves as a core hub of P2X7R-mediated injury.

NLRP3 Inflammasome Activation and Chronic Inflammation

P2X7R is a well-established upstream trigger of NLRP3 inflammasome assembly. While this pathway is prototypical in gout and CAPS, similar mechanisms operate in GBS/EAN, MS/EAE, FMF and potentially in some lysosomal storage diseases: P2X7R-mediated pore formation and K⁺ efflux facilitate NLRP3 activation and IL-1β maturation, driving Th1/Th17 polarization, glial activation and tissue damage.

Glial and Immune Cell Phenotypic Shifts

In ALS, HD and MS, P2X7R activation pushes microglia and astrocytes toward pro-inflammatory, neurotoxic phenotypes (M1-like), with increased NOX2-derived ROS and exacerbated demyelination or motor neuron death. Conversely, transient or low-level P2X7R activity may support M2-like anti-inflammatory signatures or muscle regeneration, illustrating a context-dependent dualism.

Barrier Dysfunction and Increased Tissue Vulnerability

In MS and epilepsy models, P2X7R contributes to blood–brain barrier disruption via endothelial and glial mechanisms, increasing CNS exposure to peripheral inflammatory mediators. Analogous processes may underlie blood–nerve barrier changes in GBS and CMT, facilitating immune cell infiltration and inflammatory injury.

P2RX7 Polymorphisms Shaping Disease Risk and Severity

Gain-of-function P2RX7 variants are associated with increased risk and severity in MS and may influence susceptibility and treatment responses in other RDs. This mirrors observations in basal ganglia diseases, where altered purinergic receptor expression and sensitivity modulate disease phenotypes, suggesting a more general paradigm in which genetic variation fine-tunes purinergic signaling across conditions.

Collectively, these findings support the concept that P2X7R integrates extracellular danger signals into a conserved pathological network centered on Ca²⁺, mitochondria and inflammasomes that is repeatedly “reused” across RDs. However, disease-specific factors—including the predominant P2X7R-expressing cell types, the timing and intensity of activation and interactions with primary genetic or environmental insults—determine whether P2X7R signaling is ultimately deleterious, compensatory or neutral in a given clinical context.

Conclusion and Future Directions

P2X7R occupies a strategic position at the intersection of inflammation amplification, cell death and immune regulation. Accumulating evidence links aberrant P2X7R activation or expression to the pathogenesis of multiple RDs affecting the peripheral and central nervous systems, the immune system and lysosomal function. Viewed together, these data support the notion that P2X7R-dependent pathways form a shared molecular platform across clinically heterogeneous RDs, reminiscent of the purinergic mechanisms that connect Huntington’s and Parkinson’s disease.

Several critical challenges must be addressed before P2X7R can be fully exploited as a therapeutic target: 1) The precise, context-dependent roles of P2X7R differ across diseases, cell types and stages, and the receptor often exerts both detrimental and protective effects. 2) P2X7R expression and function are influenced by genetic polymorphisms, disease stage, sex and concomitant medications, complicating both mechanistic interpretation and therapeutic design. 3) Most evidence derives from cellular and animal models, and many P2X7R antagonists have failed to meet expectations in clinical trials, highlighting translational gaps between preclinical and human studies.

Future research directions include: 1) Systematic analysis of P2X7R interactions with oxidative stress, lysosomal storage, mitochondrial dysfunction and other key pathogenic pathways using multi-omics and systems biology approaches in diverse RD models. 2) Design of CNS-penetrant, highly selective P2X7R antagonists or modulators with optimized pharmacokinetics and safety profiles to overcome the limitations of first-generation compounds. 3) Incorporation of P2RX7 genotyping and inflammatory/neurodegenerative biomarkers into patient stratification, enabling personalized selection of candidates, dosing regimens and combination therapies. 4) Use of organoids, microphysiological systems and gene-editing technologies to create models that more faithfully recapitulate human RD pathology and thereby improve predictive validity for clinical translation. 5) Rationally designed clinical trials based on comparative and translational data, with careful evaluation of dosing, timing and combination regimens, supported by coordinated efforts among academia, industry, regulatory agencies and patient organizations.

In summary, substantial progress has been made in elucidating P2X7R biology in RDs, but realizing its full therapeutic potential will require sustained, multidisciplinary efforts. Clarifying when, where and how to modulate P2X7R activity may ultimately help shift the management of selected RDs from symptomatic care toward mechanism-based, precision interventions, offering new hope for this large and historically underserved patient population.

Funding Statement

This work was supported by the Key Projects of the National Natural Science Foundation of China [Grant No. 81973969]. The principal investigator of this grant (Professor Haiyan Yin) was responsible for the conceptualization, supervision, writing – review and editing, and funding acquisition of this review. The funder had no involvement in the conduct of this review beyond financial support.

Data Sharing Statement

Data sharing is not applicable to this article as no data were created or analysed in this study.

Author Contributions

Xinyi Xiao: Conceptualization, Investigation, Writing – original draft, Data curation, Visualization.

Gege Cao and Shuai Hou: Investigation, Data curation, Writing – review & editing.

Haiyan Yin: Conceptualization, Supervision, Writing – review & editing, Funding acquisition.

All authors 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.

Disclosure

Xinyi Xiao reports Support for the manuscript from National Natural Science Foundation of China (Key Projects), during the conduct of the study.

All authors declare that the research was conducted in the absence of any other commercial or financial relationships that could be construed as a potential conflict of interest.