Lactylation in colorectal cancer: Unveiling novel mechanisms in metabolism, progression and therapeutic targeting

BACKGROUND: Colorectal cancer is a leading cause of cancer mortality characterised by a unique metabolic microenvironment and complex interactions with the gut microbiota. Lactylation, a novel post-translational modification derived from lactate, has emerged as a key epigenetic regulator connecting metabolic reprogramming to gene expression. While its general roles in cancer are recognised, the tissue-specific regulatory network of lactylation in colorectal cancer-particularly its interplay with the gut microbiome and specific chemotherapy resistance mechanisms-remains underexplored. MAIN BODY: This review systematically dissects the dynamic 'writer‒eraser‒reader' network of lactylation, highlighting its distinct oncogenic functions in colorectal cancer. We reveal a critical 'microbiome‒metabolism‒epigenetics' axis in which gut flora-derived metabolites (including D-lactate) remodel the tumour microenvironment and drive immune evasion. Beyond histone modifications, we emphasise the pivotal role of non-histone lactylation targets (e.g., eEF1A2, PD-L1) in orchestrating malignant proliferation and promoting liver metastasis by priming the pre-metastatic niche. Furthermore, we elucidate novel mechanisms by which lactylation induces resistance to standard chemotherapeutic agents (5-fluorouracil and oxaliplatin), specifically through the enhancement of DNA repair and the suppression of ferroptosis. We also critically evaluate the pharmacological challenges hindering clinical translation, such as the poor selectivity of current broad-spectrum inhibitors. SHORT CONCLUSION: Lactylation serves as a fundamental metabolic‒epigenetic link driving aggressive phenotypes in colorectal cancer. By delineating these tissue-specific mechanisms and proposing next-generation site-specific targeting strategies, this review provides a theoretical foundation for developing precision medicine interventions to overcome therapy resistance in colorectal cancer patients.