Activation-induced cytidine deaminase sustains glycolytic flux through MYST1 acetyltransferase-dependent lactylation in hepatocellular carcinoma

Hepatocellular carcinoma (HCC) exhibits profound metabolic reprogramming, yet the mechanisms that sustain persistent glycolytic flux remain poorly defined. In this study, we identify activation-induced cytidine deaminase (AID) as a non-canonical metabolic regulator that drives HCC progression through a self-reinforcing feedforward loop. AID is significantly upregulated in HCC tissues, where its expression correlates with aggressive clinical features and poor prognosis. Mechanistically, AID functions as a molecular scaffold, recruiting the acetyltransferase MYST1 via its 95 to 198 amino acid domain. This AID-MYST1 complex utilizes Lac-CoA as a substrate to mediate site-specific non-histone lactylation of the rate-limiting glycolytic enzymes GLUT1 (K6) and PGK1 (K6). These modifications markedly enhance the enzymatic activities of GLUT1 and PGK1, thereby accelerating glycolytic flux. Critically, this activation establishes a metabolic positive feedback loop: the intensified glycolysis leads to excessive lactate and Lac-CoA accumulation, which in turn fuels further AID/MYST1-dependent lactylation. This self-sustaining circuitry not only maintains high glycolytic energy production but also sequentially drives the expression of oncogenic drivers, ultimately remodeling the tumor microenvironment (TME). Functionally, disruption of the AID-MYST1-lactylation axis either through genetic ablation of lactylation sites or through pharmacological intervention effectively breaks this vicious cycle, impairing glycolysis and suppressing tumor growth in vitro and in vivo. Furthermore, dual inhibition of AID and glycolysis exerts robust synergistic antitumor effects. Collectively, our findings delineate a previously unrecognized AID-MYST1-lactylation-glycolysis axis that underpins the metabolic plasticity of HCC, offering a promising therapeutic strategy to target metabolic dependencies in liver cancer.