Tubular PFKFB3 drives diabetic kidney fibrosis via lactate‑dependent H4K12 lactylation and HIPK2 transactivation.

Authors

Mingkun Xu, Linhang Fu, Yulong Zhang, Xiuli Guo, Han Wu, Sijing Gao, Fei Xiao, Li Xu

Published in

International journal of molecular medicine. Volume 58. Issue 3. Epub Jul 17, 2026.

Abstract

Aerobic glycolysis is increasingly recognized as a pathogenic driver in diabetic kidney disease (DKD). However, the epigenetic role of its end product, lactate, remains largely undefined. Spatial transcriptomics analysis revealed active glycolysis in tubular epithelial cells. The participation of histone lactylation in DKD was confirmed through inhibition of histone lactylation by glycolysis inhibitors or lactate in vivo. The potential target genes of H4K12 lactylation (H4K12la) were screened by CUT&Tag analyses. The candidate target genes were validated through ChIP‑qPCR, RT‑qPCR and western blot analyses. The present study found that the expression of 6‑phosphofructo‑2‑kinase/fructose‑2,6‑biphosphatase 3 (PFKFB3), a pivotal glycolytic regulator, was markedly upregulated in tubular epithelial cells derived from patients with DKD and from the corresponding mouse models. Inhibition of the expression of PFKFB3 mitigated the kidney fibrotic process and alleviated renal function in a DKD mouse model. Conversely, upregulation of PFKFB3 expression aggravated renal fibrogenesis and promoted the deterioration of renal pathology. Moreover, it was demonstrated that the reduction in the levels of lactate levels markedly alleviated renal fibrosis in DKD. With regard to its mechanism of action, lactate was generated via PFKFB3‑driven glycolytic reprogramming and selectively enhanced H4K12 lactylation at the homeodomain‑interacting protein kinase 2 (HIPK2) promoter, thereby activating its transcription and driving renal fibrotic progression. These findings indicated that PFKFB3 in renal tubules upregulates HIPK2 expression via facilitating H4K12la‑dependent gene transcription. Therefore, intervention approaches targeting PFKFB3‑triggered HIPK2 activation in tubular cells may offer a novel therapeutic strategy for DKD.

PMID:
42464649
Bibliographic data and abstract were imported from PubMed on 17 Jul 2026.

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