Purinergic Signalling最新文献

{"title":"Soluble P2X7 receptor (sP2X7R) as a marker of inflammation in pregnancy.","authors":"Valentina Vultaggio-Poma, Selene Schio, Cristina Taliento, Rosa Galasso, Simonetta Falzoni, Claudia D'Angiolillo, Sara Ghisellini, Pantaleo Greco, Francesco Di Virgilio, Anna Lisa Giuliani","doi":"10.1007/s11302-026-10186-y","DOIUrl":"10.1007/s11302-026-10186-y","url":null,"abstract":"<p><p>The purinergic P2X7 receptor (P2X7R) is a key regulator of inflammation and pro-inflammatory cytokine release. Recently, a soluble form of P2X7R (sP2X7R) has been identified in the circulation of healthy individuals and significantly increased in patients with inflammatory disorders. As pregnancy is characterized by finely regulated inflammatory adaptations and considered a state of low-grade inflammation, we hypothesized that P2X7R may contribute to the physiological inflammatory status of pregnancy and to pregnancy-related inflammatory disorders. A cohort of 90 pregnant women was evaluated at the first, second, and third trimester of pregnancy, and 30 age-matched non-pregnant women were used as controls. We measured sP2X7R blood concentrations, and the neutrophil-to-lymphocyte ratio (NLR) was used as a reference inflammatory marker. Associations with maternal characteristics, pregnancy complications and foetal sex were investigated. Serum sP2X7R concentrations were significantly higher in pregnant than in control women and increased progressively throughout pregnancy. Although sP2X7R and NLR showed similar trends, sP2X7R provided complementary information. First-trimester sP2X7R concentrations were significantly higher in multigravida women, in those with gestational hypothyroidism, and in those carrying a male foetus. No significant differences were observed according to Body Mass Index (BMI), gestational diabetes, or gestational hypertension. Furthermore, sP2X7R was detectable in umbilical cord blood and positively correlated with maternal circulating concentrations. To our knowledge, this is the first study to show that circulating sP2X7R increases during normal pregnancy and reflects the physiological inflammatory adaptations of gestation. The results indicate that circulating sP2X7R is a potential biomarker of inflammatory responses and maternal-fetal immune interactions during pregnancy.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13569818/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148945751","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antagonism of P2X7 receptor function in synovial fibroblasts is a potential therapeutic manipulation in rheumatoid arthritis.","authors":"Shi-Yan Zhang, Y Tang, P Illes","doi":"10.1007/s11302-026-10181-3","DOIUrl":"10.1007/s11302-026-10181-3","url":null,"abstract":"<p><p>In a recent article published in Science Advances, Rao et al. reported that synovial fibroblasts (SFs) from patients with rheumatoid arthritis (RA) express higher levels of P2X7 receptors (P2X7Rs) than SFs from patients with osteoarthritis [1]. EVT-401, a highly selective P2X7R antagonist with a marked preference for the human ortholog, inhibited the proliferation of RA SFs isolated from inflamed synovial tissue and maintained in culture for one day. EVT-401 also induced cell-cycle arrest in the G₀/G₁ phase. Incubation of RA SFs with TNFα increased P2X7R expression and was accompanied by enhanced IL-6 secretion, which was attenuated by EVT-401. RNA sequencing of TNFα-treated RA SFs revealed that EVT-401 downregulated the expression of genes involved in inflammatory responses. In humanized animal models of RA, EVT-401 demonstrated therapeutic efficacy, exerting direct anti-invasive and cartilage-protective effects on RA SFs. In conclusion, inhibition of P2X7R function in synovial fibroblasts may represent a promising therapeutic approach for patients with drug-refractory RA.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13553991/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148912087","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Electroacupuncture and P2X receptors: purinergic mechanisms in pain modulation : A narrative review with structured evidence mapping.","authors":"Rajaa Shaheen","doi":"10.1007/s11302-026-10184-0","DOIUrl":"10.1007/s11302-026-10184-0","url":null,"abstract":"<p><p>Acupuncture and electroacupuncture (EA) are used for pain modulation, but the molecular events linking needling to analgesia remain incompletely defined. Purinergic signaling provides a biologically coherent framework because mechanical stimulation at acupoints releases extracellular adenosine triphosphate (ATP), which can activate P2X receptors and is subsequently metabolized into adenosine. Importantly, the receptor-level literature synthesized here is dominated by EA studies, whereas key local ATP-adenosine evidence derives from manual or traditional acupuncture. This review synthesizes evidence on purinergic mechanisms involved in acupuncture-related analgesia, with primary emphasis on EA modulation of P2X3, P2X4, and P2X7 receptors across dorsal root ganglion (DRG), spinal dorsal horn, and supraspinal cortical compartments, while distinguishing manual/traditional acupuncture evidence at the acupoint level. A narrative review with structured evidence mapping was conducted. The synthesis prioritizes mechanistic studies of manual/traditional acupuncture and EA in inflammatory, neuropathic, diabetic neuropathic, visceral, and cancer pain models, and integrates the limited available human data on acupoint adenosine signaling. Evidence is interpreted according to stimulation modality, receptor subtype, and anatomical compartment. The best-supported local pathway is the ATP-adenosine cascade: manual or traditional needling induces ATP release and CD39/CD73-mediated conversion to adenosine, activating anti-nociceptive adenosine A1 receptors (A1R). Most receptor-specific evidence, however, derives from EA. P2X3 receptors in nociceptive DRG neurons are the most consistently reproduced EA-associated target, with reduced receptor expression, membrane trafficking, and ATP-evoked currents. P2X4R-related evidence links EA analgesia with reduced spinal microglial activation, BDNF signaling, and central sensitization, but direct receptor-specific causal confirmation remains limited. P2X7R findings are compartment-specific and must be interpreted alongside EA stimulation parameters and the receptor's requirement for relatively high or sustained extracellular ATP exposure. Purinergic signaling offers a compelling mechanistic bridge between needling-based stimulation and pain relief. The receptor-level evidence is predominantly preclinical, male-biased, and EA-centred; manual acupuncture and EA should not be treated as mechanistically interchangeable. Human receptor-level studies, sex-balanced designs, standardized reporting of EA parameters, and direct causal interrogation of receptor function are needed before P2X modulation can be considered clinically validated.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13558502/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148920805","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Impact of cryopreservation on immune cell subset frequencies in human peripheral blood mononuclear cells following assessment of monoclonal antibodies to CD39 and P2X7.","authors":"Leon Koning, Ashleigh Splitt, Daniel Brungs, Martin G Carolan, Senthilkumar Gandhidasan, Ronald Sluyter","doi":"10.1007/s11302-026-10180-4","DOIUrl":"10.1007/s11302-026-10180-4","url":null,"abstract":"<p><p>Peripheral blood mononuclear cells (PBMCs) are commonly cryopreserved for immune cell profiling analyses, like flow cytometry. Cryopreservation of PBMCs may affect the recovery of immune cell subsets or the presence of cell-surface molecules, potentially skewing results compared to freshly isolated PBMCs. The ectonucleotidase CD39 promotes immunosuppression through the hydrolysis of extracellular nucleotides such as adenosine 5'-triphosphate (ATP) to limit P2X7 activation and downstream immune responses. Because of this, CD39 and P2X7 are emerging as potential biomarkers in cancer and other diseases. Using flow cytometry, this study demonstrated that an anti-human CD39 monoclonal antibody (mAb) (clone TU66) bound human embryonic kidney (HEK) 293 cells transfected with human CD39, but not mock-transfected HEK293 cells. In contrast, an anti-human P2X7 mAb (clone 1058613) bound similarly to HEK293 cells transfected with human P2X7 and non-transfected HEK293 cells. Using flow cytometry, this study then assessed the impact of cryopreservation on the population frequencies of immune cell subsets including CD39⁺ cells in human PBMC samples. These analyses revealed that cryopreservation had a minor, yet statistically significant impact on the population frequencies of CD4⁺, CD8⁺ and CD4^-CD8^- T cells. Cryopreservation also had a significant impact on the frequencies of CD39⁺CD19⁺ B cells and CD39⁺ non-classical monocytes. Overall, this study informs researchers and biobank workers about the need to consider the impact of cryopreservation when interpreting data from stored samples.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13550357/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148907183","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Interaction between purinergic signalling and purinergic modulators with skin wound repair effectors: a systematic review of preclinical in vivo models.","authors":"Silvânia Mól Pelinsari, Reggiani Vilela Goncalves, Patricia da Silva Mattosinhos, Mariáurea Matias Sarandy, Emerson Ferreira Vilela, Rômulo Dias Novaes","doi":"10.1007/s11302-026-10178-y","DOIUrl":"10.1007/s11302-026-10178-y","url":null,"abstract":"<p><p>Purinergic signalling plays a central regulatory role on cell proliferation, migration, differentiation, survival, and inflammation. However, the impact of purinergic modulators-based therapies on tissue repair is still overlooked. By using a systematic review framework, we investigated the therapeutic relevance of purinergic agonists and antagonists in animal models of skin wound healing. Following PRISMA guidelines, PubMed/Medline, Scopus, Web of Science, Embase, and CINAHL databases were searched, identifying 12 in vivo preclinical studies. Risk of bias was assessed using the SYRCLE tool. Topical or oral administration of CGS-21680 (4-[{N-ethyl-5'-carbamoyladenos-2-yl}aminoethyl] phenylpropionic acid), UTP (Uridine-5'-triphosphate), NECA (5'-N-ethylcarboxamidoadenosine), ATP (adenosine triphosphate), PDRN (polydeoxyribonucleotide), ADP (Adenosine-5'-diphosphate) and TMPS (Thymidine 5'-O-monophosphorothioate) agonists stimulated wound contraction, fibroblast and keratinocyte proliferation, angiogenesis, and collagen biosynthesis. These effects were associated with activation of Nrf2 (Nuclear factor erythroid 2-related factor 2), MAPK (Mitogen-Activated Protein Kinase), and ERK/CREB pathways, inflammation and oxidative/nitrosative stress down-regulation, and increased anti-inflammatory/regulatory cytokines (IL-10, IL-13, TGF-β) and growth factors (FGF, EGF). Conversely, the purinergic antagonists DMPX (3,7-dimethyl-1-propargylxanthine), CSC (8-(3-chlorostyryl) caffeine), SUR (Suramin), ENP (enprofylline), caffeine, CLOP (clopidogrel), MRS 2179 (2'-deoxy-N6-methyladenosine-3',5'-bisphosphate), and MRS 2395 (2-Chloro-3',5'-O-(benzoyl-β,γ-methylene) adenosine 5'-triphosphate), as well as genetic knockout for purinergic receptors delayed wound closure by inhibiting these pathways, impairing angiogenesis, collagenogenesis, and aggravating inflammation and oxidative damage. Purinergic agonists were associated with improved wound healing through inflammatory and oxidative modulation, enhanced angiogenesis, increased cell proliferation, and accelerated wound closure, whereas antagonists or genetic deficiency of purinergic receptors impaired tissue repair. This review was registered in the PROSPERO database (CRD420251010254).</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13530080/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148866257","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Effects on mouse melanoma and immune cells of P2X7 receptor positive allosterism by clemastine.","authors":"Maria Luiza Thorstenberg, Simonetta Falzoni, Rocio Edith Garcia-Jacobo, Leticia Scussel Bergamin, Mario Tarantini, Giulia Conversano, Anna Pegoraro, Francesco Di Virgilio, Elena Adinolfi, Anna Lisa Giuliani","doi":"10.1007/s11302-026-10179-x","DOIUrl":"10.1007/s11302-026-10179-x","url":null,"abstract":"<p><p>Clemastine (CLE), an H1R antagonist widely used for the treatment of allergic rhinitis, has recently been investigated for its positive modulatory effects on P2X7, a receptor for extracellular ATP (eATP) involved in the regulation of inflammation, immune responses, and the composition of the tumor microenvironment (TME). Here, we further examined the effects of CLE on P2X7-mediated responses to clarify the pharmacological significance of P2X7 potentiation. First, in murine and human cells expressing (B16F10 WT and HEK293-hP2X7) or lacking (B16F10 P2X7^-/- and HEK293 WT) the P2X7 receptor, we measured intracellular Ca²⁺ influx, ethidium bromide (EB) and daunorubicin (DN) uptake, mitochondrial morphology, and LDH and ATP release following P2X7 agonism or antagonism in the presence of CLE. We found that CLE increased Bz-ATP-induced P2X7-mediated channel opening, pore formation, mitochondrial remodeling, eATP release, and cell death, effects absent in P2X7-null cells and abolished by P2X7 antagonists. As a readout of activation of NLRP3 inflammasome, a known downstream effector of the P2X7 receptor, we also assessed the effect of CLE on IL-1β release from peritoneal macrophages from wild-type (WT) or P2X7 knockout (KO) mice, LPS-primed and treated with ATP and/or CLE. We found that the combined treatment significantly increased IL-1β release from P2X7-WT macrophages compared to the two stimuli administered separately. On the whole, our results demonstrate that CLE can effectively positively modulate P2X7 function, suggesting new opportunities for its therapeutic exploitation.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13525124/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148851003","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Differential expression, activity, and fibroblast growth factor 2-mediated modulation of purine-metabolizing enzymes in cultured cortical astrocytes and microglia.","authors":"Ryota Eguchi, Ken-Ichi Otsuguro","doi":"10.1007/s11302-026-10177-z","DOIUrl":"10.1007/s11302-026-10177-z","url":null,"abstract":"<p><p>Extracellular purines such as adenosine triphosphate and adenosine, serve as important neurotransmitters and modulators in the central nervous system. Extracellular purine concentrations are tightly regulated by a series of purine-metabolizing enzymes that convert adenosine triphosphate into adenosine and inosine. Both astrocytes and microglia, major glial cells in the central nervous system, contribute to extracellular purine metabolism; however, the differences in the expression profiles, enzymatic activities, and regulatory mechanisms of purine-metabolizing enzymes between these cells remain incompletely understood. In this study, we compared the expression levels and enzymatic activities of purine-metabolizing enzymes in cultured rat cortical astrocytes and microglia, and further examined their regulatory pathways. Microglia exhibited higher expression and activity of purine-metabolizing enzymes compared with astrocytes. Fibroblast growth factor 2 regulated the expression and activity of purine-metabolizing enzymes in astrocytes through pathways dependent on fibroblast growth factor receptors and mitogen-activated protein kinases, whereas such regulation was not observed in microglia. These findings highlight the pivotal role of microglia in central nervous system purine metabolism and suggest that fibroblast growth factor 2 modulates purine metabolism in a cell type-specific manner.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 5","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-08-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13522313/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148841189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The P2X7 receptor: insights from the murine monoclonal antibody clone L4.","authors":"Ronald Sluyter, Amal Elhage, Rachael Bartlett, Debbie Watson, Leanne Stokes, Kristen K Skarratt, Stephen J Fuller, Ben J Gu","doi":"10.1007/s11302-026-10176-0","DOIUrl":"10.1007/s11302-026-10176-0","url":null,"abstract":"<p><p>The P2X7 receptor (or P2X7) is an ATP-gated ion channel with important roles in the immune and other body systems. Much has been garnered about P2X7 using the first published anti-human P2X7 monoclonal antibody (mAb) (clone L4). This mAb can be used to impair P2X7 channel and pore activity and events downstream of P2X7 activation in vitro and in vivo. Immunolabelling with this mAb has been used in flow and mass cytometry, confocal microscopy and immunohistochemistry to help establish the presence of P2X7 on human leukocytes and other primary cell types, as well as various malignant cell lines. This mAb has been applied to immunoprecipitate P2X7 to identify co-associated molecules to help uncover novel roles of the receptor such as phagocytosis. Recently, this mAb has been shown to mediate complement-dependent cytotoxicity, offering a new avenue of limiting P2X7-mediated processes by depleting P2X7⁺ cells. Finally, this mAb has been used to identify and characterise polymorphic and other variants of P2X7. This article will discuss the origins and various applications of the anti-P2X7 mAb (clone L4). As an early user of this mAb and pioneer of other purinergic technologies, this article is a tribute to the late Francesco Di Virgilio.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13400550/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148584973","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Is adenosine signalling entering the precision medicine era? From receptor pharmacology to patient stratification.","authors":"Luca Antonioli, György Haskó","doi":"10.1007/s11302-026-10175-1","DOIUrl":"10.1007/s11302-026-10175-1","url":null,"abstract":"<p><p>Over the past three decades, adenosine signalling has emerged as a fundamental regulatory system controlling immune responses, tissue homeostasis, metabolism, and repair processes. The identification of four adenosine receptor subtypes and the development of selective agonists and antagonists generated substantial enthusiasm for therapeutic targeting across a broad spectrum of inflammatory, autoimmune, metabolic, and neoplastic diseases. However, despite compelling preclinical evidence, the clinical translation of adenosine-based therapies has often yielded inconsistent or disappointing results. Increasing evidence suggests that these limitations may not primarily reflect inadequate pharmacological tools, but rather an incomplete understanding of the remarkable spatial, temporal, and cellular heterogeneity of adenosine signalling in human disease. Advances in immunology, systems biology, single-cell technologies, spatial transcriptomics, metabolomics, and artificial intelligence are revealing highly diverse purinergic landscapes across tissues and patient populations. These findings challenge the traditional \"one receptor-one disease\" paradigm and support a transition toward precision medicine approaches capable of identifying disease-specific and patient-specific purinergic signatures. In this commentary, we discuss how the field is moving beyond classical receptor pharmacology toward biomarker-driven patient stratification. We propose that the next generation of purinergic therapeutics will depend not only on improved drugs but also on the ability to define when, where, and in whom adenosine signalling should be manipulated. Such a shift may ultimately represent the long-awaited bridge between decades of successful experimental research and meaningful clinical implementation.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13379558/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148472523","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammation, oxidative stress and purinergic signaling in pituitary neuroendocrine tumors (PitNETs).","authors":"Yenidis Teilor Scheibel, Symon Martins, André Paulo Turcatel, Francini Franscescon, Débora Tavares de Resende E Silva","doi":"10.1007/s11302-026-10174-2","DOIUrl":"10.1007/s11302-026-10174-2","url":null,"abstract":"<p><p>Pituitary neuroendocrine tumors (PitNETs) constitute a heterogeneous group of intracranial neoplasms with variable biological behavior, whose aggressiveness cannot be explained solely by the intrinsic characteristics of tumor cells. Growing evidence demonstrates that chronic inflammation of the tumor microenvironment (TME) plays a central role in the progression, invasiveness, therapeutic resistance, and recurrence of these tumors. In this context, the purinergic system emerges as a fundamental regulatory axis of the local inflammatory response, integrating signals derived from cellular stress, hypoxia, and metabolic reprogramming. The extracellular release of ATP under conditions of oxidative stress, tissue damage, and cell death serves as a pro-inflammatory signal by activating P2 purinergic receptors. On the other hand, its conversion to adenosine by the ectonucleotidases CD39 and CD73 promotes an immunosuppressive environment, mainly through P1 receptors, such as A2A and A2B. This dynamic balance modulates the infiltration and polarization of immune cells, the production of inflammatory cytokines, including IL-6, IL-8, and TNF-α, the activation of transcriptional pathways such as NF-κB, STAT3, and HIF-1α, and extracellular matrix remodeling and angiogenesis. This study aims to review the role of inflammation in the tumor microenvironment of PitNETs, with emphasis on purinergic signaling as an integrating link between oxidative stress, immune dysfunction, and metabolic reprogramming. Although not abundantly explored, the purinergic pathway in PitNETs shows promising potential: it interconnects different elements of the TME, contributes to tumor mechanisms, and is a potential target for immunomodulatory and anti-inflammatory therapies in pituitary tumors.</p>","PeriodicalId":20952,"journal":{"name":"Purinergic Signalling","volume":"22 4","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13341977/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148397254","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}