Lactylation at the crossroads: a metabolic-epigenetic-immune integrator in intestinal homeostasis and disease.

Abstract

Lysine lactylation (Kla) is a metabolite-sensitive post-translational modification implicated in DNA repair, tumorigenesis, chemoresistance, and innate immunity. Recent studies also implicate Kla in intestinal disorders. This review synthesizes current evidence on protein lactylation in intestinal inflammation, inflammatory bowel disease, colorectal cancer, irritable bowel syndrome, intestinal fibrosis, radiation-induced injury, and enteric infection. We distinguish lactate-mediated receptor signaling and metabolic effects from covalent Kla, compare evidence across cell types and disease stages, and assess preclinical strategies targeting the lactate-lactylation axis. We also discuss microbiota-host metabolic crosstalk and mucus-penetrating nanodelivery, including the cross-border emulsification effect, an oil-in-water double-emulsion concept that describes traversal of the mucus barrier rather than a biochemical form of lactylation. Collectively, the available evidence supports a metabolism-epigenetics-immunity framework for gut pathophysiology, while highlighting unresolved questions concerning stereochemistry, site specificity, causality, safety, and prospective clinical validation.