Nonhistone lactylation: A hub for tumour metabolic reprogramming and epigenetic regulation.

Recent research has shifted the perception of lactate from being merely a byproduct of metabolism to being a crucial signalling molecule and epigenetic regulator in tumours. This paper provides a comprehensive review of the mechanisms by which the lactylation of nonhistones contributes to tumorigenesis and tumour development. Lactate accumulates in the tumour microenvironment (TME) due to the Warburg effect and serves as a substrate for the covalent modification of nonhistone proteins (such as p53 and PD-L1) through both enzymatic and nonenzymatic processes. These modifications influence gene expression, signalling pathways, autophagy, and DNA damage repair, ultimately facilitating tumour growth, metastasis, and immune evasion. This review also discusses how the lactylation of nonhistones contributes to the chemotherapy and immunotherapy resistance of tumours by increasing homologous recombination repair, bolstering antioxidant defences, and fostering an immunosuppressive environment. Furthermore, therapeutic strategies targeting key enzymes involved in lactate metabolism (such as LDH and MCTs) and those related to lactylation (such as AARS1 and the SIRT family) are explored. Potential applications of glycolysis inhibitors (e.g., 2-DG), lactate transport inhibitors (e.g., α-CHC), and specific activators of depyrogenase are discussed. Future research should focus on the spatiotemporal dynamics of lactylation and the development of targeted interventions to enhance tumour combination therapies.