Objective:To investigate the effects of DGCR8 on the proliferation, migration, invasion and tumorigenic ability of melanoma cells and its downstream pathway. Methods:Public datasets, including GSE115978, GSE72056 and TCGA-SKCM, were integrated to analyze the expression characteristics, proliferation-related features and prognostic significance of DGCR8 in melanoma. A DGCR8 knockdown model was established in A375 cells, followed by RNA sequencing and enrichment analysis to identify differentially enriched pathways and candidate molecules after DGCR8 knockdown. BCKDHA knockdown and BCKDHA rescue models in the context of DGCR8 knockdown were constructed. mRNA and protein expression, as well as cell proliferation, migration and invasion, were examined. The NAD?/NADH ratio was detected using the WST-8 method, and a nude mouse xenograft assay was performed to evaluate the effect of BCKDHA rescue on the phenotype induced by DGCR8 knockdown. Results:Single-cell sequencing database analysis showed that DGCR8 was highly expressed in melanoma cells and was associated with active cell proliferation. Deconvolution-based survival analysis showed that high DGCR8 expression was associated with poor prognosis. Cellular experiments showed that DGCR8 knockdown inhibited the proliferation, migration and invasion of A375 cells, and led to decreased AKT phosphorylation at Ser473 and Thr308, an increased NAD?/NADH ratio and downregulated BCKDHA expression. BCKDHA rescue restored AKT phosphorylation, proliferation, migration and invasion in DGCR8-knockdown cells and enhanced their tumorigenic ability in vivo. After BCKDHA knockdown, AKT phosphorylation decreased and the NAD?/NADH ratio increased, showing the same direction of change as that observed after DGCR8 knockdown. Conclusion:Our study supports that DGCR8 can regulate AKT phosphorylation and NADH metabolism via BCKDHA, thereby promoting the proliferation, migration, invasion, and tumorigenesis of A375 cells.