Targeting Lactylation: From Metabolic Reprogramming to Precision Therapeutics in Liver Diseases

Lactylation, a recently identified post-translational modification (PTM) triggered by excessive lactate accumulation, has emerged as a crucial regulator linking metabolic reprogramming to pathological processes in liver diseases. In hepatic contexts, aberrant lactylation contributes to a range of pathological processes, including inflammation, dysregulation of lipid metabolism, angiogenesis, and fibrosis. Importantly, lactylation has been shown to impact tumor growth, metastasis, and therapy resistance by modulating oncogene expression, metabolic adaptation, stemness, angiogenesis, and altering the tumor microenvironment (TME). This review synthesizes current knowledge on the biochemical mechanisms of lactylation, encompassing both enzymatic and non-enzymatic pathways, and its roles in specific liver diseases. From a therapeutic perspective, targeting lactate availability and transport, as well as the enzymes regulating lactylation, has demonstrated promise in preclinical models. Additionally, combinatorial approaches and natural compounds have shown efficacy in disrupting lactylation-driven pathways, providing insights into future research directions for hepatic diseases. Although the emerging role of lactylation is gaining attention, its spatiotemporal dynamics and potential for clinical translation are not yet well comprehended. This review aims to synthesize the multifaceted roles of lactylation, thereby bridging mechanistic insights with actionable therapeutic strategies for liver diseases.