Lactate metabolism-driven lactylation: paradoxical modulation of intestinal inflammation and malignancy

Intestinal inflammation and malignancy represent two critical pathological states in the gut that severely impair patients’ quality of life. Understanding their molecular mechanisms holds significant therapeutic implications. Lactate plays a key role in cellular signaling and immune regulation. Lactylation, a modification mediated by lactate, plays a key role in epigenetic regulation. Targeting lactate metabolism and lactylation has emerged as a promising intervention strategy for intestinal diseases. This review summarizes the basic framework of the lactate metabolic system and the biological functions of lactate and lactylation, with a focus on the core mechanisms of lactylation in intestinal inflammation and malignancy. Lactylation exerts a context-dependent “paradoxical modulation” role. In intestinal inflammation, as exemplified by inflammatory bowel disease, lactylation drives macrophage phenotypic conversion, mediates gut microbiota-host interactions, regulates fibrosis progression, and modulates intestinal inflammation and tissue repair. Colorectal cancer, a major form of intestinal malignancy, is promoted by lactylation through mechanisms including immunosuppression, malignant proliferation, drug resistance, and tumor metastasis. Finally, we discuss the basis of the paradoxical modulation role of lactylation and explore the therapeutic potential of targeting lactate metabolism and lactylation as novel treatment strategies. In summary, this review highlights lactylation as a central player in intestinal diseases, providing insights into the pathomechanisms of intestinal inflammation and colorectal cancer. Lactate metabolism and lactylation hold significant potential as therapeutic targets for intestinal inflammation and malignancy, providing a promising path for precise intervention strategies in intestinal diseases.