Forkhead Box Protein K1 Promotes Chronic Kidney Disease by Driving Glycolysis in Tubular Epithelial Cells

Abstract

AbstractRenal tubular epithelial cells (TECs) undergo an energy‐related metabolic shift from fatty acid oxidation to glycolysis during chronic kidney disease (CKD) progression. However, the mechanisms underlying this burst of glycolysis remain unclear. Herein, a new critical glycolysis regulator, the transcription factor forkhead box protein K1 (FOXK1) that is expressed in TECs during renal fibrosis and exhibits fibrogenic and metabolism‐rewiring capacities is reported. Genetic modification of the Foxk1 locus in TECs alters glycolytic metabolism and fibrotic lesions. A surge in the expression of a set of glycolysis‐related genes following FOXK1 protein activation contributes to the energy‐related metabolic shift. Nuclear‐translocated FOXK1 forms condensate through liquid‐liquid phase separation (LLPS) to drive the transcription of target genes. Core intrinsically disordered regions within FOXK1 protein are mapped and validated. A therapeutic strategy is explored by targeting the Foxk1 locus in a murine model of CKD by the renal subcapsular injection of a recombinant adeno‐associated virus 9 vector encoding Foxk1‐short hairpin RNA. In summary, the mechanism of a FOXK1‐mediated glycolytic burst in TECs, which involves the LLPS to enhance FOXK1 transcriptional activity is elucidated.