The glycolytic enzyme PFKM promotes renal fibrosis by activating the NF-κB pathway via lactate-mediated H3K18 lactylation.

Abstract

Glycolytic reprogramming is closely associated with chronic kidney disease (CKD) progression. However, the role and mechanism of phosphofructokinase muscle type (PFKM), a core rate-limiting enzyme in glycolysis, in renal fibrosis remain unclear. This study analyzed Gene Expression Omnibus (GEO) datasets of renal tissues from patients with CKD to construct a folic acid (FA)-induced mouse model of renal fibrosis. PFKM overexpression or knockdown was achieved specifically in renal tubular epithelial cells using an adeno-associated virus serotype 9 (AAV9) vector. Additionally, combined with a transforming growth factor-β1 (TGF-β1)-stimulated human kidney-2 (HK-2) cell model, the underlying mechanism was explored via histological staining, metabolic analysis, ribonucleic acid (RNA) sequencing (RNA-seq), cleavage under targets and tagmentation (CUT&Tag), and chromatin immunoprecipitation-quantitative polymerase chain reaction (ChIP-qPCR). The results showed that PFKM was significantly upregulated in the renal tissues of patients with CKD and in fibrotic mice, exhibiting a positive correlation with fibrosis markers. Functional experiments demonstrated that PFKM knockdown alleviated FA-induced renal fibrosis in mice, whereas PFKM overexpression exacerbated fibrosis. Mechanistically, PFKM drives glycolytic reprogramming, leading to lactate accumulation. Lactate promotes histone H3 lysine 18 lactylation (H3K18la) at the Rela promoter through modifications, thereby activating the nuclear factor-κB (NF-κB) pathway and ultimately exacerbating renal inflammation and fibrosis. Collectively, PFKM promotes renal fibrosis through the "glycolysis-lactate-H3K18la-NF-κB" axis, identifying it as a novel therapeutic target for CKD.