BRAF and melanoma: 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).