Fig. 1: Reprogrammed glucose metabolism and l-, d- and s-lactylation.

Compared with normal cells, cancer cells accelerate glycolysis by inducing different isozymes of glycolytic enzymes. Lactate, the end product of glycolysis, causes l-lactylation on lysine residues of target proteins by HATs or AARS. G3P or DHAP, the intermediate metabolites of glycolysis, upregulate LGSH, which causes d-lactylation on lysine residues of target proteins by NECMs. In addition, G3P causes s-lactylation on cysteine residues of target proteins by NECMs. Enzymes that catalyze metabolic reactions are depicted inside yellow ovals. Enzymes that are frequently induced in cancer cells are written in red inside yellow ovals. The precursor metabolites for lactylation are written in red. The enzymes that catalyze lactylation are depicted in green ovals. The thickness of the arrows represents the relative flux. 2PG, 2-phosphoglycerate; 3PG, 3-phosphoglycerate; α-KG, α-ketoglutarate; ALDO, aldolase; ENO, enolase; F1,6BP, fructose-1,6-bisphosphate; F2,6BP, fructose-2,6-bisphosphate; F6P, fructose-6-phosphate; G6P, glucose-6-phosphate; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; GLUT, glucose transporter; GPI, glucose-6-phosphate isomerase; HK, hexokinase; MCT, monocarboxylate transporter; OAA, oxaloacetate; PEP, phosphoenolpyruvate; PFKFB, 6-phosphofructo 2-kinase/fructose-2,6-bisphosphatase; PGAM1, phosphoglycerate mutase 1; PGK1, phosphoglycerate kinase 1; PK, pyruvate kinase; TCA, tricarboxylic acid; TPI, triose phosphate isomerase.