The lactate-lactylation axis in renal fibrosis: potential mechanisms in diabetic kidney disease

Disturbances in energy metabolism are increasingly recognized as a key factor in the development of diabetic kidney disease (DKD). Among the pathological features of advanced DKD, renal fibrosis is both common and irreversible. With growing insight into metabolic reprogramming, lactate and its epigenetic derivative-lactylation-have gained attention as potential modulators of disease progression.

A systematic literature search was conducted in databases including PubMed, Embase, and Web of Science using keywords such as 'lactate', 'lactylation', 'diabetic kidney disease', 'renal fibrosis', and 'metabolic reprogramming'. Studies were included if they focused on the association between lactate/lactylation and DKD-related renal fibrosis, with priority given to preclinical (animal models, cell experiments) and clinical (human biopsy, cohort studies) evidence. Exclusion criteria were non-relevant studies, duplicates and articles with insufficient data.

In DKD, elevated lactate levels are associated with altered energy metabolism (enhanced glycolysis, impaired mitochondrial oxidative phosphorylation), inflammation activation (macrophage polarization, pro-inflammatory cytokine release), and excessive extracellular matrix deposition in renal tissues. Quantitatively, studies have shown that urinary lactate levels in DKD patients are 2.3-3.5 times higher than those in healthy controls, and lactate concentrations >2.5 mM can suppress mitochondrial oxidative phosphorylation in proximal tubular epithelial cells. Through lactylation modification, lactate regulates the activity of key molecules: histone lactylation (e.g. H3K14la) modulates the transcription of fibrosis-related genes, while non-histone lactylation (including PKM2, Fis1, Twist, Snail lactylation) affects glycolytic enzyme activity, mitochondrial function, and epithelial-mesenchymal transition, collectively contributing to renal fibrosis.

The lactate-lactylation axis is closely associated with renal fibrosis progression in DKD, and targeting this axis offers a promising therapeutic strategy to potentially slow fibrosis and preserve renal function in DKD. Consequently, inhibiting lactate dehydrogenase A, modulating monocarboxylate transporters, or targeting lactylation enzymes may provide novel treatment avenues. However, current evidence remains largely correlative, underscoring the need for large-scale cohort studies and early-phase clinical trials to validate its translational potential.