LDHA Lactylation Drives Malignant Progression of Oral Squamous Cell Carcinoma via a Positive Feedback Loop with Lactate.

Lysine lactylation (Kla) is an emerging post-translational modification closely linked to glycolysis, where it functions to regulate the activity of glycolytic enzymes. In oral squamous cell carcinoma (OSCC), elevated expression of Lactate dehydrogenase A (LDHA) drives lactate production, thereby supplying the substrate for Kla. Nevertheless, whether LDHA itself undergoes Kla in OSCC has yet to be explored. Here, we have conclusively verified that LDHA undergoes high-level Kla in OSCC tissues and cells, with its Kla abundance positively associated with intracellular lactate concentrations. Both in vitro and in vivo analyses collectively illustrated that LDHA-K318 lactylation functions as a crucial driver of OSCC malignant progression. Functionally, our investigations revealed that the LDHA-K318R mutation diminishes lactate generation and decreases global protein Kla levels. GCN5 acts as an upstream "writer" that coordinately regulates LDHA-Kla, thereby modulating lactate production and facilitating OSCC malignancy. Furthermore, we identified HDAC1 as an "eraser" that governs LDHA-Kla status. Combined administration of the GCN5 inhibitor MB-3 and the LDHA-K318 lactylation-targeting peptide (K318-pe) remarkably inhibited tumor growth in the PDX models. Our study uncovers a positive feedback loop linking lactate and glycolysis, mediated by LDHA-Kla in OSCC. This discovery implicates lactylation-associated regulators as viable therapeutic targets, opening novel perspectives for clinical application.