Lactylation in cancer: Metabolic-epigenetic nexus and therapeutic frontiers

The revolutionary discovery of histone lactylation fundamentally reshapes our understanding of cancer metabolism, revealing how glycolytic lactate directly orchestrates protein modification. This review comprehensively synthesizes mounting evidence positioning lactylation as a critical, yet paradoxically dual, regulator of oncogenic processes. While often driving malignant phenotypes through mechanisms like MRE11-K673la-mediated DNA repair, lactylation can also exert tumor-suppressive effects, such as H3K18la-induced cell cycle arrest, highlighting its context-dependent complexity. We delve into the paradigm-shifting discovery of alanyl-tRNA synthetases (AARS1/2) as novel, CoA-independent lactylation catalysts, challenging long-held assumptions. Furthermore, we systematically dissect lactylation's intricate crosstalk with other post-translational modifications, unveiling competitive dynamics with acetylation (e.g., H3K18la vs. H3K18ac) and cooperative metabolic coupling with m6A methylation. Beyond fundamental mechanisms, this review illuminates the profound clinical potential of lactylation. We discuss how specific lactylation patterns, including histone (H4K12la) and non-histone (p53-K120la) modifications, emerge as promising biomarkers correlating with drug response across diverse malignancies. Addressing critical gaps, we establish a robust conceptual framework for lactylation as a dynamic metabolic sensor and propose actionable strategies for therapeutic targeting, paving the way for novel precision oncology approaches. This work bridges fundamental insights to translational applications, propelling forward the emerging and impactful field of metabolic-epigenetic regulation in cancer.