ATP-P2X3 Signaling as a Shared Neural Sensitization Pathway in Endometriosis and Irritable Bowel Syndrome: Mechanisms and Therapeutic Implications

Endometriosis and IBS frequently coexist and exhibit substantial clinical overlap (see Figure 1 ), often making accurate diagnosis challenging [ 7 ]. Both disorders commonly present with chronic pelvic and abdominal pain, bloating, altered bowel habits, dyschezia, and symptom exacerbation during periods of physiological stress or menstruation, leading to frequent misdiagnosis and delays in appropriate management [ 8 , 26 ]. Women with endometriosis have a significantly higher prevalence of IBS than the general population, highlighting a close clinical association between these conditions [ 7 ]. Beyond their overlapping symptomatology, both disorders are characterized by visceral hypersensitivity [ 27 , 28 ], peripheral and central sensitization [ 29 , 30 ], and neuroimmune dysregulation [ 31 , 32 ], suggesting shared mechanisms of chronic pain generation. This convergence has drawn increasing attention toward common nociceptive pathways, particularly ATP-mediated activation of P2X3 receptors, which may contribute to persistent sensory neuron activation and represent a promising therapeutic target for treating chronic pelvic and visceral pain in patients with endometriosis and IBS.

Purinergic signaling is a fundamental mechanism of intercellular communication that regulates inflammation, nociception, and tissue homeostasis [ 33 ]. Under physiological conditions, intracellular ATP functions primarily as the cell’s energy currency. However, tissue injury, inflammation, hypoxia, mechanical stress, and cellular damage trigger the extracellular release of ATP through pannexin and connexin hemichannels or from damaged cells [ 34 ]. Once released, ATP acts as a danger-associated molecular pattern (DAMP), activating purinergic receptors expressed on sensory neurons, immune cells, epithelial cells, and glial cells [ 35 ]. Extracellular ATP contributes to neurogenic inflammation by stimulating the release of pro-inflammatory cytokines, chemokines, and neuropeptides while simultaneously increasing the excitability of primary afferent neurons [ 34 ]. Although ATP activates both metabotropic P2Y receptors and ionotropic P2X receptors, increasing evidence indicates that P2X3 receptors are particularly important mediators of chronic inflammatory and visceral pain [ 36 ]. This makes them attractive therapeutic targets for disorders characterized by persistent nociceptive signaling [ 37 ]. Purinergic dysregulation encompasses a broad spectrum of abnormalities in extracellular nucleotide metabolism and receptor signaling rather than activation of a single receptor [ 38 ]. Reduced ectonucleotidase activity, increased extracellular ATP accumulation, and altered expression of multiple purinergic receptors collectively contribute to a pro-inflammatory and pronociceptive microenvironment. Within this broader network, activation of P2X3 receptors on primary sensory neurons represents a downstream mechanism that specifically mediates peripheral nociceptor activation and pain transmission [ 39 ]. Thus, while purinergic dysregulation contributes to disease pathophysiology, P2X3-mediated nociception represents one of its principal functional consequences. The P2X receptor family comprises seven ATP-gated ion channel subtypes (P2X1–P2X7), with P2X3 being one of the principal receptors involved in nociception [ 40 ]. P2X3 receptors are predominantly expressed on small- and medium-diameter sensory neurons within the dorsal root, trigeminal, and nodose ganglia, where they detect extracellular ATP released during tissue injury and inflammation [ 13 ]. Functional receptors exist as homotrimeric P2X3 channels or heterotrimeric P2X2/3 receptors, both of which are highly permeable to sodium and calcium ions [ 40 ]. Activation of P2X3 receptors produces rapid membrane depolarization, calcium influx, and action potential generation, facilitating transmission of nociceptive signals from peripheral tissues to the central nervous system [ 25 ]. Beyond neuronal excitation, P2X3 activation promotes the release of neurotransmitters and neuropeptides that further amplify inflammatory signaling [ 41 ]. Persistent receptor activation therefore contributes to sustained neuronal hyperexcitability, a hallmark of chronic pain disorders [ 36 ]. The structural distinction between homomeric P2X3 and heteromeric P2X2/3 receptors has guided the development of selective antagonists, with newer agents designed to minimize P2X2/3 inhibition to reduce taste-related adverse effects [ 42 ]. Peripheral sensitization, characterized by increased nociceptor responsiveness following tissue injury or inflammation, and central sensitization, resulting from enhanced excitability within spinal pain pathways, are both amplified by ATP–P2X3 signaling [ 29 ]. Inflammatory mediators such as prostaglandins, NGF, bradykinin, histamine, and pro-inflammatory cytokines promote ATP release and P2X3 receptor upregulation, creating a positive feedback loop that enhances synaptic transmission and promotes chronic visceral hypersensitivity [ 43 ]. Experimental models of endometriosis and IBS consistently demonstrate increased ATP release, elevated P2X3 receptor expression, and enhanced sensory neuron excitability, supporting dysregulated ATP–P2X3 signaling as a shared mechanism of chronic pelvic and visceral pain and highlighting selective P2X3 inhibition as a promising therapeutic strategy [ 44 ].

Endometriosis is increasingly recognized as a neuroinflammatory disorder characterized by chronic activation of immune and sensory pathways [ 45 ]. In endometriosis, purinergic dysregulation extends beyond P2X3 receptor activation and includes impaired extracellular ATP metabolism, altered ectonucleotidase activity, and activation of multiple purinergic receptor subtypes that collectively sustain inflammation and tissue remodeling [ 46 ]. Ectopic endometrial lesions recruit macrophages, mast cells, and other immune cells that release pro-inflammatory cytokines, prostaglandins, nerve growth factor (NGF), and chemokines, creating a persistent inflammatory microenvironment that promotes neuroangiogenesis, peripheral nerve remodeling, and increased nociceptor excitability [ 47 ]. Sustained inflammation lowers nociceptor activation thresholds, leading to peripheral sensitization, while persistent nociceptive input induces DRG plasticity and central sensitization, mechanisms that contribute to chronic pelvic pain and symptom persistence even after surgical excision of endometriotic lesions [ 48 ]. Importantly, pain severity does not consistently correlate with lesion burden alone, and emerging evidence suggests that lesion location, the extent of adhesions, and central pain sensitization may be more closely associated with symptom severity [ 49 , 50 ]. Inflammation and tissue injury within endometriotic lesions promote the extracellular release of ATP from damaged epithelial, stromal, immune, and sensory nerve cells, where it functions as a danger-associated molecular pattern that activates ATP-gated P2X receptors on primary afferent neurons, amplifying inflammatory pain signaling [ 51 ]. Among these receptors, P2X3 is of particular interest because of its predominant expression on nociceptive sensory neurons and its established role in chronic inflammatory pain [ 52 ]. Experimental studies demonstrate increased P2X3 receptor expression in DRG innervating endometriotic lesions, leading to enhanced neuronal excitability, calcium influx, neurotransmitter release, visceral hypersensitivity, and sustained nociceptive transmission, thereby establishing a positive feedback loop that perpetuates chronic pelvic pain [ 53 ]. The proposed ATP–P2X3 signaling pathway underlying peripheral and central sensitization in endometriosis is summarized in Figure 2 .

Visceral hypersensitivity is a defining feature of IBS and is considered a major contributor to chronic abdominal pain [ 54 ]. Patients with IBS exhibit heightened perception of physiological intestinal stimuli, reflecting increased excitability of primary afferent neurons and altered pain processing within the gut–brain axis [ 55 ]. Persistent low-grade inflammation, epithelial barrier dysfunction, and repeated luminal stimulation promote the release of ATP and other inflammatory mediators that sensitize nociceptive pathways [ 34 ]. Activation of P2X3 receptors on visceral afferent neurons lowers activation thresholds, facilitating exaggerated pain responses and contributing to the maintenance of chronic visceral hypersensitivity [ 56 ]. IBS is increasingly recognized as a neuroimmune disorder in which bidirectional communication between immune cells, enteric neurons, and the intestinal epithelium sustains chronic pain [ 57 ]. Increased mast cell activation, macrophage infiltration, and elevated levels of inflammatory mediators, including histamine, serotonin, cytokines, prostaglandins, and ATP, have been reported in subsets of patients with IBS [ 58 ]. Extracellular ATP released during intestinal inflammation activates P2X3 receptors expressed on sensory neurons, amplifying nociceptive signaling and promoting neurogenic inflammation. Interactions between ATP–P2X3 signaling and other pain mediators, including NGF, TRPV1, and CGRP, further enhance neuronal excitability and contribute to persistent abdominal pain [ 59 ]. The proposed ATP–P2X3 signaling pathway underlying visceral hypersensitivity in IBS is summarized in Figure 3 .

The frequent coexistence of endometriosis and IBS suggests that chronic pain may arise through shared neurobiological mechanisms rather than independent disease processes [ 7 ]. One proposed mechanism is cross-organ sensitization, whereby persistent nociceptive input from one pelvic organ enhances pain perception in adjacent organs through convergent neural pathways. In endometriosis, continuous stimulation from ectopic lesions may sensitize visceral afferents supplying the gastrointestinal tract, contributing to IBS-like symptoms [ 60 ]. Conversely, chronic intestinal inflammation and visceral hypersensitivity may amplify pelvic pain through similar mechanisms. ATP released during tissue injury and inflammation is likely to contribute to this process by activating P2X3 receptors on shared sensory neurons, thereby facilitating persistent nociceptive transmission between pelvic organs [ 61 ]. The DRG serves as a critical integration center for sensory input from pelvic and abdominal organs. Sustained activation of primary afferent neurons induces structural and functional plasticity within the DRG, including increased expression of ion channels, neurotransmitters, and purinergic receptors [ 62 ]. Experimental models have demonstrated upregulation of P2X3 receptors in DRG neurons following chronic inflammatory stimulation, resulting in enhanced neuronal excitability and prolonged pain signaling [ 43 ]. These changes may underlie the transition from acute inflammation to chronic pelvic and visceral pain and provide a mechanistic basis for the persistent symptoms observed in both endometriosis and IBS. Neuroimmune interactions play a central role in maintaining chronic pain in both disorders. Activated macrophages, mast cells, T lymphocytes, and other immune cells release cytokines, chemokines, prostaglandins, and ATP, which sensitize peripheral nociceptors and perpetuate inflammation [ 58 ]. In turn, activated sensory neurons locally release neuropeptides, including substance P and CGRP, further promoting immune cell activation and neurogenic inflammation [ 63 ]. This bidirectional communication establishes a self-sustaining inflammatory cycle that enhances neuronal excitability and chronic pain [ 64 ]. ATP-mediated activation of P2X3 receptors represents an important interface between immune activation and nociceptive signaling, positioning purinergic signaling as a potential therapeutic target capable of interrupting this pathogenic feedback loop [ 64 ]. Although ATP–P2X3 signaling plays an important role in chronic pelvic and visceral pain, it functions within a broader neuroimmune network involving mediators such as NGF, TRPV1, CGRP, ASICs, prostaglandins, bradykinin, and substance P, which collectively amplify neuronal activation, peripheral sensitization, and neurogenic inflammation [ 48 , 65 , 66 ]. In particular, NGF promotes P2X3 receptor expression and sensory nerve sprouting, while TRPV1 and ASICs enhance nociceptor responsiveness to inflammatory stimuli [ 65 , 67 ]. Despite these complex interactions, the selective expression of P2X3 receptors on nociceptive sensory neurons and encouraging preclinical findings make ATP–P2X3 signaling an attractive therapeutic target, warranting further investigation of selective P2X3 antagonists alone or in combination with complementary therapies for endometriosis- and IBS-associated chronic pain [ 61 , 68 ]. The proposed shared ATP–P2X3-mediated pathway underlying cross-organ sensitization, DRG plasticity, neuroimmune crosstalk, and chronic visceral pain is summarized in Figure 4 . The key experimental studies supporting ATP–P2X3 signaling as a shared neural sensitization pathway linking endometriosis and IBS are summarized in Table 1 .

The selective expression of P2X3 receptors on nociceptive sensory neurons makes them an attractive therapeutic target for chronic pain. Unlike conventional analgesics, P2X3 antagonists selectively inhibit ATP-mediated activation of primary afferent neurons, reducing peripheral sensitization while minimizing the gastrointestinal, cardiovascular, and dependency-related adverse effects associated with nonsteroidal anti-inflammatory drugs (NSAIDs) and opioids [ 78 ]. Experimental studies in endometriosis and IBS demonstrate that ATP-mediated P2X3 activation drives persistent nociceptive signaling, DRG hyperexcitability, and visceral hypersensitivity, providing a strong biological rationale for P2X3 inhibition as a novel therapeutic strategy [ 79 ]. However, because central sensitization may become established in chronic disease, early intervention or combination therapy may be required to achieve optimal clinical outcomes [ 21 ]. Although preclinical studies provided an initial rationale for targeting P2X3 signaling, the phase 2b SCHUMANN trial has since evaluated the selective P2X3 antagonist eliapixant in women with endometriosis-associated pelvic pain [ 77 ]. Although the study did not demonstrate significant efficacy over placebo and was terminated early because of safety concerns, it represents the first clinical evaluation of P2X3 antagonism in endometriosis and provides important translational evidence for this therapeutic strategy [ 77 ]. Numerous experimental studies demonstrate the analgesic potential of selective P2X3 antagonists, with pharmacological inhibition or genetic downregulation of P2X3 reducing nociceptor excitability, ATP-induced neuronal activation, DRG hyperexcitability, and central sensitization [ 79 ]. In animal models of endometriosis and IBS, P2X3 blockade attenuates pelvic pain, inflammatory responses, and visceral hypersensitivity, providing consistent preclinical evidence that ATP–P2X3 signaling is a key mediator of chronic pain and a promising therapeutic target [ 61 ]. Gefapixant is the first selective P2X3 receptor antagonist to receive regulatory approval for the treatment of refractory or unexplained chronic cough, validating P2X3 receptors as clinically relevant therapeutic targets [ 80 ]. It has received regulatory approval in Japan for refractory chronic cough, although the US FDA issued a Complete Response Letter, highlighting the importance of balancing efficacy and tolerability in P2X3 antagonist development [ 80 ]. Clinical trials have demonstrated significant reductions in cough frequency and improvements in patient-reported quality of life [ 21 ]. However, because gefapixant also inhibits heteromeric P2X2/3 receptors involved in taste perception, dysgeusia and ageusia have emerged as the most common adverse effects, limiting treatment adherence in some patients [ 81 ]. Nevertheless, the clinical success of gefapixant provides proof of concept that selective modulation of ATP-mediated sensory signaling can effectively treat disorders characterized by neuronal hypersensitivity. Eliapixant is a highly selective P2X3 antagonist developed to improve receptor specificity while minimizing taste-related adverse effects observed with earlier compounds [ 22 ]. Phase II clinical studies have demonstrated encouraging efficacy in chronic cough with a substantially lower incidence of dysgeusia compared with gefapixant [ 22 ]. The improved selectivity of eliapixant makes it an attractive candidate for chronic pain conditions requiring long-term treatment, including disorders associated with persistent visceral hypersensitivity [ 82 ]. Although newer P2X3 antagonists were developed to reduce taste-related adverse effects, dysgeusia has not been completely eliminated [ 83 ]. This may reflect residual inhibition of P2X2/3 receptors at therapeutic doses, a potential role of P2X3 receptors in taste signaling, and differences in receptor occupancy, pharmacokinetics, and individual susceptibility [ 84 ]. These observations suggest that receptor selectivity alone may not fully predict tolerability and warrant further investigation. Sivopixant is another next-generation P2X3 antagonist designed to retain therapeutic efficacy while improving tolerability through greater receptor selectivity [ 23 ]. Clinical studies have reported reductions in cough frequency with relatively few taste disturbances, suggesting that selective inhibition of P2X3 receptors without significant P2X2/3 blockade may improve the overall safety profile [ 18 ]. Although its clinical evaluation has focused primarily on chronic cough, the underlying mechanism of sensory neuron inhibition supports potential application in chronic pelvic and visceral pain syndromes. Camlipixant is a potent and highly selective P2X3 antagonist currently undergoing clinical evaluation for refractory chronic cough and other hypersensitivity disorders [ 24 ]. Early clinical studies have demonstrated meaningful reductions in cough frequency with improved tolerability compared with less selective antagonists [ 85 ]. The favorable balance between efficacy and adverse effects highlights the continued refinement of P2X3-targeted therapies and supports further investigation of this drug class for disorders characterized by peripheral sensory neuron hyperexcitability [ 86 ]. Filapixant is a potent and highly selective P2X3 receptor antagonist that has been investigated for the treatment of refractory chronic cough [ 87 ]. In a phase 2 randomized crossover trial, filapixant significantly reduced cough frequency and severity while improving cough-related quality of life, supporting the role of P2X3 inhibition in attenuating sensory neuron hyperexcitability [ 88 ]. Although the drug was generally well tolerated, dose-dependent taste disturbances remained common, particularly at higher doses, suggesting that receptor selectivity alone may not fully eliminate this class-related adverse effect [ 88 ]. Nevertheless, the demonstrated clinical efficacy of filapixant further validates P2X3 receptor antagonism as a promising therapeutic strategy for disorders characterized by peripheral sensory hypersensitivity [ 89 ]. Collectively, the clinical development of P2X3 antagonists demonstrates that ATP-mediated sensory signaling is a viable therapeutic target [ 90 ]. Although these agents have primarily been developed for chronic cough, the shared mechanisms of peripheral sensitization, neuroimmune activation, and neuronal hyperexcitability observed in endometriosis and IBS suggest considerable potential for drug repurposing [ 91 ]. As summarized in Table 2 , currently available P2X3 antagonists—including gefapixant, eliapixant, sivopixant, and camlipixant—have advanced through Phase II to IV clinical development and exhibit favorable safety profiles, with taste disturbance (dysgeusia) representing the principal adverse effect [ 22 , 23 , 24 , 81 , 87 , 90 ]. Future clinical trials should evaluate whether selective P2X3 inhibition can reduce chronic pelvic and visceral pain, identify patient populations most likely to benefit, and determine whether combination therapy targeting complementary nociceptive pathways provides greater clinical efficacy than P2X3 inhibition alone. The clinical development of P2X3 antagonists for refractory chronic cough provides a promising opportunity for drug repurposing in endometriosis and IBS, which share features of sensory neuron hyperexcitability, neuroimmune activation, and visceral hypersensitivity [ 90 ]. By selectively inhibiting ATP-mediated afferent pain signaling, P2X3 antagonists may offer a nonhormonal, mechanism-based approach for managing chronic pelvic and abdominal pain, particularly in patients with persistent symptoms after surgery, predominant visceral hypersensitivity, or overlapping endometriosis and IBS. Successful clinical translation will require careful patient selection, biomarker-guided stratification, and evaluation using pain-specific outcomes, while combination therapies targeting complementary pathways such as TRPV1, NGF, CGRP, hormonal signaling, or the microbiome may further improve therapeutic efficacy [ 65 , 66 ]. Despite growing interest in P2X3 antagonists, several challenges remain before their integration into the management of endometriosis and IBS. Most evidence supporting ATP–P2X3 signaling is derived from preclinical studies, while direct clinical evidence of P2X3 upregulation in patients remains limited [ 37 , 41 , 90 ]. Chronic pelvic and visceral pain are also multifactorial, involving hormonal influences, inflammation, neuropathic mechanisms, myofascial dysfunction, and interacting pathways such as TRPV1, NGF, CGRP, ASICs, prostaglandins, and cytokines. Consequently, P2X3 inhibition alone may not provide complete symptom relief, particularly in patients with established central sensitization, highlighting the need for biomarker-guided patient selection and combination therapeutic strategies [ 36 ]. Additional challenges include optimizing dosing, treatment duration, predictors of response, and clinical endpoints, as well as establishing long-term safety, particularly for newer, more selective P2X3 antagonists developed to minimize taste disturbances associated with first-generation agents [ 86 ]. The effects of hormonal fluctuations, disease stage, and coexisting disorders of gut–brain interaction also require further investigation. Nevertheless, the clinical success of P2X3 antagonists in refractory chronic cough demonstrates that ATP-mediated sensory signaling is a clinically actionable pathway, providing a strong rationale for biomarker-driven clinical trials evaluating selective P2X3 inhibition as a precision therapy for endometriosis- and IBS-associated chronic pain [ 90 ].

The successful clinical translation of P2X3-targeted therapies will depend on the identification of reliable biomarkers that reflect purinergic pathway activation and predict therapeutic response [ 92 ]. Current evidence is insufficient to determine which patients with endometriosis or IBS exhibit clinically significant ATP–P2X3 dysregulation. Future studies should investigate circulating inflammatory mediators, extracellular ATP levels, purinergic receptor expression, transcriptomic signatures, and neuroimaging biomarkers as potential tools for patient stratification. The integration of molecular biomarkers with quantitative sensory testing and patient-reported outcomes may facilitate earlier diagnosis and improve treatment selection. Endometriosis and IBS are biologically heterogeneous disorders, suggesting that not all patients will respond similarly to P2X3 inhibition. Precision medicine approaches integrating clinical phenotypes, molecular biomarkers, genomic profiling, and disease endotypes may identify patient populations most likely to benefit from targeted therapy [ 57 ]. Individuals with overlapping endometriosis and IBS, persistent visceral hypersensitivity, or evidence of enhanced neuroimmune activation may represent particularly suitable candidates for future clinical trials [ 27 , 28 ]. Combining P2X3 antagonists with hormonal therapies, neuromodulators, biologics, or microbiome-directed interventions may further improve therapeutic outcomes by targeting multiple mechanisms involved in chronic pain [ 93 ]. Despite growing evidence implicating ATP–P2X3 signaling in chronic pain, several important knowledge gaps remain. Most available data originate from experimental models, whereas direct clinical evidence demonstrating P2X3 upregulation in patients with endometriosis, IBS, or coexisting disease is limited [ 77 , 93 ]. Large, prospective translational studies are needed to validate the role of purinergic signaling in disease pathogenesis and determine whether P2X3 receptor expression correlates with symptom severity, disease progression, or treatment response. Future randomized clinical trials should evaluate selective P2X3 antagonists in endometriosis and IBS using standardized pain measures, quality-of-life assessments, biomarkers of neuroimmune activation, and objective indices of visceral hypersensitivity. Addressing these gaps will determine whether ATP–P2X3 signaling represents not only a shared mechanistic pathway but also a clinically actionable target capable of improving personalized management of chronic pelvic and visceral pain.

Although accumulating evidence supports a role for ATP–P2X3 signaling in chronic pelvic and visceral pain, most mechanistic data are derived from animal models and in vitro studies, with relatively limited clinical evidence directly evaluating P2X3 receptor expression or activity in endometriosis and IBS. Furthermore, substantial heterogeneity in experimental models, disease induction methods, diagnostic criteria, pain assessment, and laboratory techniques, together with small sample sizes and predominantly cross-sectional study designs, limits direct comparisons and the translation of preclinical findings to clinical practice. Chronic pelvic and visceral pain also arise from multiple interacting mechanisms involving TRPV1, NGF, CGRP, ASICs, inflammatory cytokines, hormonal influences, and gut microbiota alterations, indicating that ATP–P2X3 signaling represents one component of a complex neuroimmune network rather than a single causal pathway [ 15 , 59 , 67 ]. Clinical evidence supporting the therapeutic use of P2X3 antagonists in endometriosis and IBS remains limited. Table 3 summarizes the current evidence available. Although these agents have demonstrated efficacy in refractory chronic cough, their effectiveness, optimal dosing, long-term safety, and appropriate patient selection for chronic pelvic and visceral pain have yet to be established. Nevertheless, the available evidence consistently identifies ATP–P2X3 signaling as a key contributor to neuroimmune pain mechanisms, supporting further translational studies and randomized clinical trials to determine whether selective P2X3 inhibition can be developed into a precision therapy for patients with endometriosis and IBS.

Endometriosis and irritable bowel syndrome (IBS) are common chronic disorders that substantially impair quality of life, contribute to significant healthcare utilization, and impose considerable socioeconomic burden worldwide [ 1 ]. Endometriosis affects approximately 10% of women of reproductive age and is characterized by the ectopic implantation of endometrial-like tissue, resulting in chronic pelvic pain, dysmenorrhea, dyspareunia, infertility, and gastrointestinal symptoms [ 2 ]. Similarly, IBS is one of the most prevalent disorders of gut–brain interaction, affecting an estimated 5–10% of the global population and presenting with recurrent abdominal pain, altered bowel habits, bloating, and visceral hypersensitivity [ 3 , 4 ]. Although they are distinct clinical entities, accumulating evidence suggests that these conditions frequently coexist and may share overlapping mechanisms of chronic pain generation [ 5 ]. The coexistence of endometriosis and IBS is increasingly recognized in clinical practice [ 6 ]. Women with endometriosis are significantly more likely to meet diagnostic criteria for IBS than the general population, and gastrointestinal symptoms frequently persist even after surgical treatment of endometriotic lesions [ 7 ]. These observations suggest the presence of shared biological mechanisms, although the pathways responsible for symptom persistence remain incompletely understood [ 8 ]. Chronic pain in both endometriosis and IBS is believed to arise from complex interactions among peripheral inflammation, immune activation, visceral hypersensitivity, and central nervous system sensitization [ 9 , 10 ]. Multiple molecular mediators, including transient receptor potential vanilloid 1 (TRPV1), nerve growth factor (NGF), calcitonin gene-related peptide (CGRP), substance P, acid-sensing ion channels (ASICs), and purinergic receptors, have been implicated in nociceptive signaling [ 11 , 12 , 13 , 14 , 15 ]. Among these pathways, purinergic signaling through the P2X3 receptor has emerged as a particularly compelling candidate because of its well-established role in sensory neuron activation, inflammatory pain transmission, and peripheral sensitization [ 16 ]. Extracellular adenosine triphosphate (ATP), released during tissue injury, inflammation, hypoxia, or cellular stress, functions as an important extracellular signaling molecule by activating P2X receptors expressed on primary sensory neurons, immune cells, and peripheral nerve terminals, thereby promoting neuronal excitability and amplifying nociceptive transmission [ 17 , 18 ]. Among the seven P2X receptor subtypes, P2X3 plays a central role in the initiation and maintenance of inflammatory and neuropathic pain [ 19 ]. Experimental studies have demonstrated that increased ATP release and P2X3 receptor activation contribute to visceral hypersensitivity in gastrointestinal disorders and chronic pelvic pain models, highlighting the receptor as a potential therapeutic target [ 20 ]. The development of selective P2X3 antagonists has renewed interest in purinergic signaling as a clinically actionable pathway [ 21 , 22 , 23 , 24 ]. Although these agents have primarily been investigated for refractory chronic cough, their ability to attenuate sensory neuron hyperexcitability suggests potential applications in chronic visceral pain disorders, including endometriosis and IBS [ 25 ]. Nevertheless, the current evidence remains heterogeneous and is derived predominantly from experimental and animal studies. Thus, this narrative review critically examines the available experimental and clinical evidence supporting ATP–P2X3 signaling as a shared mechanism linking endometriosis and IBS. We evaluated the therapeutic potential of P2X3 antagonists, discussed the limitations of the current evidence, and highlighted priorities for future translational and clinical research.

Endometriosis and IBS frequently coexist and share key pathophysiological features, including neuroinflammation, visceral hypersensitivity, peripheral and central sensitization, and neuroimmune activation. Current experimental evidence suggests that ATP-mediated activation of P2X3 receptors contributes to these processes by enhancing sensory neuron excitability and amplifying nociceptive signaling, supporting ATP–P2X3 signaling as a plausible shared mechanism underlying chronic pelvic and visceral pain. Selective P2X3 antagonists have demonstrated the therapeutic potential of targeting purinergic signaling and may offer a promising nonhormonal, nonopioid approach for treating chronic pain in endometriosis and IBS. However, clinical translation remains limited by the lack of robust human data, highlighting the need for studies validating P2X3 receptor expression, identifying predictive biomarkers, and establishing long-term efficacy and safety. Collectively, ATP–P2X3 signaling provides a biologically plausible framework linking endometriosis and IBS and represents one of the most promising emerging targets for precision therapies aimed at chronic pelvic and visceral pain.