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Melanoma exhibits significant resistance to conventional apoptosis-based therapies, underscoring the need for alternative strategies to induce cancer cell death. Pyroptosis is a pro-inflammatory form of programmed cell death characterized by caspase-1 activation, gasdermin D cleavage, and interleukin-1β (IL-1β) release. In this study, transcriptomic analysis revealed that aripiprazole induces robust inflammatory signaling in melanoma cells. The antipsychotic drug aripiprazole was found to trigger pyroptosis in BRAF-mutant melanoma cells, leading to caspase-1 activation, gasdermin D cleavage, and increased secretion of pro-inflammatory cytokines. Aripiprazole treatment also activated the MAPK signaling cascade and induced G1 cell-cycle arrest. Notably, aripiprazole rapidly upregulated the expression of nucleotide-binding oligomerization domain-containing protein 2 (NOD2), an innate immune receptor that acts upstream of inflammasome activation and simultaneously regulates MAPK and NF-κB signaling pathways. Genetic and pharmacological evidence demonstrated that NOD2 is essential for aripiprazole-induced pyroptosis and downstream signal propagation. This study provides mechanistic insight into the anti-cancer potential of aripiprazole and supports the broader investigation of serotonergic drugs as immunomodulatory agents in cancer therapy.