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Melanoma is an aggressive malignancy characterized by high metastatic potential and resistance to conventional therapies. Emerging evidence suggests that purinergic P2X receptors, particularly P2X7, play critical roles in regulating tumor cell proliferation, apoptosis, and invasion. However, the transcriptional regulation of P2X receptor subtypes in response to therapeutic compounds remains incompletely characterized. This study aimed to investigate the transcriptional modulation of all seven P2X receptor subtypes (P2XR1-7) in G361 melanoma cells following exposure to selected phenolic compounds and chemotherapeutic agents. Cell viability was evaluated by MTT assay, and half-maximal inhibitory concentrations (IC₅₀) were determined using non-linear regression analysis in GraphPad Prism software. Chemotherapeutic agents, including paclitaxel and sunitinib, exhibited strong cytotoxic effects under the experimental conditions employed, whereas phenolic compounds (quercetin, retinoic acid, and resveratrol) demonstrated moderate anti-proliferative activity. Quantitative real-time PCR analyses revealed compound-specific transcriptional response patterns. Quercetin induced upregulation across multiple P2X receptor subtypes, retinoic acid exhibited a partially suppressive profile, and resveratrol showed selective downregulation. In contrast, chemotherapeutic agents generally induced mRNA upregulation, particularly in P2XR4, P2XR5, and P2XR7 subtypes. These findings demonstrate that P2X receptor genes are differentially modulated at the transcriptional level by natural and synthetic compounds. The present work provides a transcriptional framework identifying subtype-specific response patterns and nominates candidate P2X receptors for future protein-level and functional validation studies in melanoma.