Overexpression of NMNAT3 suppresses melanoma progression by reprogramming NAD⁺ metabolism

Background: Melanoma represents a highly aggressive and metastatic form of malignant skin cancer. that remains challenging to treat clinically. Tumor cells often reprogram nicotinamide adenine dinucleotide (NAD⁺) metabolism to meet the demands of rapid proliferation and metastasis, however, its function and mechanism in melanoma remain unclear. Materials and Methods: Key NAD⁺ metabolism-related genes associated with melanoma were screened using bioinformatic analysis of public databases (GEO and TCGA). Weighted Gene Co-expression Network Analysis (WGCNA) and machine learning approaches, further pinpointed NMNAT3 as a critical target for subsequent research. Confirmation of NMNAT3 expression on A375 melanoma cell line by qRT-PCR. Functional assays, including CCK-8 for proliferation, scratch wound for migration, and transwell for invasion, were employed to determine the roles of NMNAT3 in melanoma cells. Furthermore, an immune cell infiltration analysis was conducted to examine the association of NMNAT3 expression with the tumor immune microenvironment. Results: Bioinformatic analyses indicated a downregulation of NMNAT3 in melanoma tissues and cell lines, demonstrating significant diagnostic potential. Moreover, Immunoanalysis shows important links between NMNAT3 expression and invasive levels of various immunologic types within the melanoma tumour microenvironment. Subsequent in vitro functional studies further showed that that NMNAT3 overexpression can significantly inhibit the malignant phenotype of melanoma cells. Conclusions: This study is the first to reveal the inhibitory role of NMNAT3 in melanoma growth. This study ensures an understanding of the theoretical principles of melanoma metabolic regulation and NMNAT3 treatment strategies.