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

ABSTRACT: Persistently enhancement of glycolytic activity has been increasingly implicated as a key contributor to the development of diabetic kidney disease (DKD). 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. Mechanistically, lactate generated via PFKFB3-driven glycolytic reprogramming selectively enhances H4K12 lactylation at the HIPK2 promoter, thereby activating its transcription and driving renal fibrotic progression. These findings suggest that tubular PFKFB3 enhancing HIPK2 expression by promoting H4K12la-mediated gene transcription. Thus, targeting the PFKFB3-mediated HIPK2 activation in renal tubular cells could be a novel strategy for DKD.

ORGANISM(S): Homo sapiens

PROVIDER: GSE328635 | GEO | 2026/04/22

REPOSITORIES: GEO

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