Figure 9.
AID/MYST1-mediated lactylation of GLUT1 and PGK1 establishes a metabolic feedforward loop to sustain the Warburg effect, the TME and tumor progression in HCC. Enhanced aerobic glycolysis (Warburg effect) in HCC leads to excessive lactate accumulation, providing lactyl-CoA as a substrate for the AID/MYST1 complex. This complex catalyzes non-histone lactylation of the key glucose uptake enzyme GLUT1 at lysine 6 (K6), and the key glycolytic enzymes PGK1 at lysine 6 (K6) and lysine 17 (K17). Lactylation of GLUT1 and PGK1 enhances glycolytic flux and further lactate production, thereby reinforcing aerobic glycolysis. Elevated lactate levels subsequently promote the expression of cancer-associated genes, including AICDA, which encodes AID. Increased AID expression, in turn, amplifies GLUT1 and PGK1 lactylation, forming a positive metabolic feed-forward loop. This self-sustaining circuit drives HCC progression by modulating the immune cell infiltrating to TME.