The role of lactate and lactylation in diabetic nephropathy

Diabetic nephropathy (DN) is a significant complication of diabetes mellitus driven by pathological mechanisms that include inflammation, oxidative stress, fibrosis, and metabolic dysregulation. Emerging evidence highlights the role of lactate metabolism and associated post-translational modification, lactylation, as important contributors to the progression of DN. Lactate exacerbates inflammation through enhancing NLRP3 inflammasome activation. Lactate also drives epithelial-mesenchymal transition, ultimately leading to renal fibrosis. Furthermore, lactate promotes apoptosis through multiple pathways in DN. Lactylation, a novel epigenetic modification that links lactate to cellular signaling, impairs endothelial function, antioxidant responses and DNA repair, and promotes fibrotic process, further aggravating DN. This review systematically elucidates the role of lactate and lactylation as important regulatory factors from the aspects of lactate metabolism and protein lactylation modification in DN. In conclusion, lactate and lactylation have important clinical significance as well as possible therapeutic potential for DN.