Cutaneous melanoma remains an aggressive malignant neoplasm characterized by molecular heterogeneity and therapeutic resistance, highlighting the need to identify alternative pathways involved in tumor progression. Purinergic signaling, particularly the conversion of extracellular ATP to immunosuppressive adenosine mediated by ectonucleotidases CD39 (NTPDase1) and CD73 (ecto-5′-nucleotidase), has emerged as a critical determinant of melanoma biology, but its potential regulation by melatonin remains unexplored.Here, we investigated whether pharmacological melatonin (0.1–5 mM, 24 and 48 h) influences metabolic activity, mitochondrial homeostasis, and extracellular nucleotide metabolism in two human melanoma cell lines with distinct molecular profiles (SK-MEL-28 and A375). Melatonin reduced metabolic activity and induced mitochondrial depolarization in both cell lines, although A375 cells exhibited greater mitochondrial sensitivity than SK-MEL-28 cells. These mitochondrial alterations were accompanied by distinct apoptosis- and inflammation-related transcriptional responses, indicating lineage-dependent cellular response to pharmacological melatonin. In parallel, melatonin differentially altered extracellular nucleotide metabolism and CD39/CD73 gene expression, with distinct responses observed between the two melanoma cell lines. Collectively, these findings indicate that the biological effects of pharmacological melatonin extend beyond mitochondrial dysfunction and involve remodeling of extracellular nucleotide metabolism, providing new evidence for an interaction between melatonergic and purinergic signaling in melanoma.
Obesity is a chronic, low-grade inflammatory condition expressed by inflammation and immune damage that mediates component(s) of insulin resistance and cardiometabolic syndrome in the presence of disruption of circadian rhythms. Primary research data indicate that the interplay between biological timing and immunological signalling occurs in a synchronised manner to govern metabolic homeostasis, thereby leading us to coin the term Circadian regulation of metabolic inflammation. These signalling pathways directly affect immune cell trafficking and endothelial integrity in sphingosine-1-phosphate receptor 1 (S1PR1) or purinergic P2X7 receptor (P2X7)–mediated regulation, and inflammasome activation. This review highlights a new molecular link establishing the S1PR1–P2X7 axis between circadian rhythm and obesity-linked immunometabolic disorders. We discuss the interplay of lipid and purinergic signalling, focusing on their convergence at nuclear factor kappa B (NF-κB), phosphoinositide 3-kinase/protein kinase B (PI3K/Akt), signal transducer and activator of transcription 3 (STAT3), reactive oxygen species (ROS), and NOD-, LRR-, and pyrin domain-containing protein 3 (NLRP3) activation pathways that act in concert to exacerbate both fatty tissue inflammation and systemic insulin metabolic resistance. Altogether, we summarise the latest advances in receptor-based pharmacotherapy, chronotherapy, and nanomedicine-guided drug delivery aimed at restoring circadian homeostasis and metabolic balance. Understanding the circadian regulation of the S1PR1–P2X7 axis may inform new precision treatment strategies for obesity-linked metabolic diseases.
Purinergic signaling has been widely recognized as a critical regulator of tumor progression, yet the role of P2Y14R in cervical cancer remains unclear. This study used the P2Y14R antagonist PPTN in in vitro cell experiments; the results showed that it significantly inhibited cell proliferation and increased LDH release. The anti-tumor effect of P2Y14R antagonism was further validated using a cervical cancer organoid model. Mechanistically, PPTN treatment elevated intracellular cAMP levels, enhanced the phosphorylation of PKA and CREB, and thereby activated the cAMP/PKA/CREB signaling axis. Moreover, PPTN intervention reduced Ki67 expression in cervical cancer organoids without affecting CK13 expression, suggesting that the anti-tumor effect of PPTN may not mediated through regulation of differentiation. Collectively, these findings identify P2Y14R as a novel regulator of the cAMP/PKA/CREB signaling pathway in cervical cancer cells, providing a promising therapeutic target for cervical cancer.
Alzheimer’s disease (AD) is the most common cause of dementia worldwide and is characterized by progressive cognitive decline, amyloid-β deposition, tau pathology, neuroinflammation, and neuronal loss. Current therapies provide only limited symptomatic benefit, and although anti-amyloid monoclonal antibodies have demonstrated disease-modifying potential in selected patients, additional disease-modifying targets are still needed. The purinergic P2X7 receptor (P2X7R), an ATP-gated ion channel predominantly expressed on microglia and astrocytes, has emerged as a key regulator of neuroinflammatory signalling and AD progression. This narrative review summarizes and critically discusses recent preclinical, translational, and clinical evidence published through 2026. Evidence from cellular and animal models, post-mortem human brain analyses, positron emission tomography (PET) imaging studies, and pharmacological investigations was evaluated to assess the role of P2X7R in AD pathogenesis and therapeutic intervention. Accumulating evidence demonstrates that extracellular ATP-mediated activation of P2X7R promotes NLRP3 inflammasome assembly, caspase-1 activation, and the release of pro-inflammatory cytokines, including interleukin-1β and interleukin-18, thereby sustaining chronic neuroinflammation. Genetic deletion or pharmacological inhibition of P2X7R reduced amyloid plaque burden, attenuated tau hyperphosphorylation, improved synaptic function, and ameliorated cognitive deficits in experimental AD models. Human studies further revealed elevated P2X7R expression and increased neuroinflammatory activity associated with AD pathology. Emerging therapeutic approaches include selective P2X7R antagonists, natural-product modulators, RNA-based interventions, nanotechnology-assisted drug delivery systems, and combination therapies targeting multiple pathogenic pathways. P2X7R represents a promising candidate target for disease-modifying therapeutic strategies in AD, based on convergent in vitro, animal-model, human post-mortem, and imaging/biomarker evidence linking ATP-mediated danger signalling to neuroinflammation, amyloid and tau pathology, and neurodegeneration. However, its clinical efficacy in AD remains to be established, as no clinical trial data for P2X7R-targeted therapies in this disease are yet available. Future clinical translation will require improved CNS-penetrant antagonists, enhanced receptor selectivity, biomarker-guided patient stratification, and precision medicine approaches.
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.
