# Delactylase effects of SIRT3 on a positive feedback loop involving the RUNX1-glycolysis-histone lactylation in diabetic kidney disease

## TL;DR

This study explores how SIRT3 and RUNX1 influence glycolysis and histone lactylation in diabetic kidney disease, offering new insights into its progression and treatment.

## Contribution

The study identifies a novel positive feedback loop involving RUNX1, glycolysis, and histone lactylation regulated by SIRT3 in DKD.

## Key findings

- Elevated glycolysis in tubular epithelial cells leads to lactate accumulation and histone lactylation in DKD.
- RUNX1 promotes glycolysis by activating HK1 and SLC2A1, which exacerbates renal fibrosis.
- Reduced SIRT3 expression in DKD enhances fibrosis by deacetylating RUNX1 and attenuating glycolysis.

## Abstract

Background: Persistently elevated glycolysis is increasingly recognized as a driving force in diabetic kidney disease (DKD). As a product of glycolysis, lactate can induce histone lactylation, an emerging epigenetic mechanism associated with post-transcriptional modification. However, the molecular mechanism and clinical impact of histone lactylation in DKD remain largely understood.

Methods and Results: Spatial transcriptomics analysis revealed upregulation of glycolytic genes in tubular epithelial cells (TECs), thus leading to elevated levels of renal lactate accumulation. PKM2 deficiency lowered the lactate production during the fibrotic process and decreased histone lactylation. Mechanistically, ChIP-seq & RNA-seq results showed lactate promoted histone H4 lysine 12 lactylation (H4K12la), which in turn enhanced RUNX1 transcription. RUNX1 subsequently activated HK1 and SLC2A1, which accelerated glycolysis and renal fibrosis of DKD. Further, SIRT3 expression was significantly decreased in the renal tubular cells in DKD. Furthermore, insufficient SIRT3 is functionally promote renal fibrosis by directly deacetylating RUNX1 at H4K12, leading to attenuated glycolytic process, and subsequently robust glycolytic ability and increased production of lactate.

Conclusion: Thus, the study links RUNX1-mediated glycolysis to SIRT3-mediated histonelactylation epigenetic reprogramming in promoting the fibrotic process, providing better understanding of epigenetic regulation of DKD pathogenesis, and new therapeutic strategy for DKD.