By using a shRNA library covering the known metabolism-related enzymes and protein factors in the human genome, 3-hydroxy-3-methylglutaryl-CoA (HMGCL), the rate-limiting enzyme implicated in ketogenesis, is identified as a “synthetic lethal” partner of BRAF mutation in melanoma cells.206 To be specific, mutant BRAF can transcriptionally upregulate HMGCL via Oct-1, and the end product of ketogenesis acetoacetate (AA) catalyzed by HMGCL further promotes the interaction between BRAFV600E and MEK1 to amplify MAPK activation (Fig. 6). This evidence concerns the gene HMGCL and melanoma.