Mounting evidence suggests that cellular metabolites,in addition to being sources of fuel and macromolecular substrates,are actively involved in signaling and epigenetic regulation.Many metabolites,such as cyclic AMP,which regulates phosphorylation/dephosphorylation, have been identified to modulate DNA and histone methylation and protein stability.Metabolite-driven cellular regulation occurs through two distinct mechanisms:proteins allosterically bind or serve as substrates for protein signaling pathways,and metabolites covalently modify proteins to regulate their functions.Such novel protein metabolites include fumarate,succinyl-CoA,propionyl-CoA, butyryl-CoA and crontonyl-CoA.Other metabolites,includingα-ketoglutarate,succinate and fumarate,regulate epigenetic processes and cell signaling via protein binding.Here,we summarize recent progress in metabolite-derived post-translational protein modification and metabolite-binding associated signaling regulation.Uncovering metabolites upstream of cell signaling and epigenetic networks permits the linkage of metabolic disorders and human diseases,and suggests that metabolite modulation may be a strategy for innovative therapeutics and disease prevention techniques. Mounting evidence suggests that cellular metabolites, in addition to being sources of fuel and macromolecular substrates, are actively involved in signaling and epigenetic regulation. Many metabolites, such as cyclic AMP, which regulates phosphorylation / dephosphorylation, have been identified to modulate DNA and histone methylation and protein stability. Metabolite-driven cellular regulation occurs through two distinct mechanisms: proteins allosterically bind or serve as substrates for protein signaling pathways, and metabolites covalently modify proteins to regulate their functions. Novel novel protein metabolites include fumarate, succinyl-CoA, propionyl- CoA, butyryl-CoA and crontonyl-CoA.Other metabolites, including α-ketoglutarate, succinate and fumarate, regulate epigenetic processes and cell signaling via protein binding. Here, we summarize recent progress in metabolite-derived post-translational protein modification and metabolite-binding associated signaling regulation. Uncovering metabolites up stream of cell signaling and epigenetic networks permits the linkage of metabolic disorders and human diseases, and suggests that metabolite modulation may be a strategy for innovative therapeutics and disease prevention techniques.