PFKFB3 promotes kidney fibrosis through histone lactylation-mediated HIPK2 activation in diabetic kidney disease

Lactate, the end product of glycolysis, can trigger histone lactylation, —an emerging epigenetic modification involved in regulating gene expression, yet its functional significance in DKD remains largely unclear. Here, we observed that 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3), a key glycolytic enzyme, was remarkably induced in tubular epithelial cells (TECs) in both DKD patients and mice model.

Inhibition the expression of PFKFB3 mitigated kidney fibrosis, and preserved kidney function in DKD mice model. Conversely, upregulation of PFKFB3 aggravates renal fibrogenesis and promotes the deterioration of renal pathology. Moreover, we demonstrated that reducing the lactate levels markedly alleviated renal fibrosis in DKD.