Lactylation at the crossroads of immune metabolism and epigenetic regulation: revealing its role in rheumatic immune diseases.

BACKGROUND: Lactate was traditionally regarded as merely the end product of glycolysis; however, recent discoveries of lactylation have revealed that lactate can also directly serve as a substrate for epigenetic modification, filling a critical gap in the understanding of "metabolite-epigenetic regulation." In rheumatic immune diseases such as rheumatoid arthritis and systemic lupus erythematosus, the affected tissues, including the joint synovium and internal organs, are typically hypoxic. These regions demonstrate pronounced inflammatory infiltration and metabolic reprogramming, leading to the accumulation of lactate within the local microenvironment. In this context, lactylation directly links the metabolic state (lactate levels) of the microenvironment with epigenetic regulation of gene expression. This offers valuable insights into how metabolic cues specifically modulate the functions of immune cells, including polarization, activation, and cytokine secretion, as well as the behavior of tissue-resident cells, such as synovial fibroblasts. Conventional immunosuppressants demonstrate limited efficacy in correcting such metabolic abnormalities; thus, exploring novel mechanisms and therapeutic targets at the intersection of metabolism and epigenetics is urgently needed. Investigating the mechanistic role of lactylation, therefore, represents a crucial step toward developing innovative therapies for rheumatic autoimmune disorders. METHODS: This review systematically summarizes the pivotal functions of lactylation within the immune-metabolic and epigenetic regulatory networks, examining its influence on metabolic pathways, chromatin modification, and disease progression. Furthermore, it discusses the modulatory roles of lactylation in immune cell activity, signaling pathway activation, and the generation of disease-specific modification patterns. RESULTS: In summary, current evidence indicates that lactylation serves as a molecular bridge connecting "immunometabolism-epigenetic dysregulation-chronic inflammation." Its tissue specificity and diverse modification substrates contribute to a complex regulatory network. Therefore, targeting the lactylation regulatory axis may enable the conversion of pathological metabolic features into therapeutic opportunities. CONCLUSION: Future research should emphasize single-cell lactylome profiling and the development of tissue-specific delivery systems to elucidate better and control the dual physiological and pathological functions of lactylation.