Inhibition of asparagine synthetase effectively retards polycystic kidney disease progression

(Figure presented.) Metabolic Reprogramming, such as glycolysis and glutaminolysis, are key features of polycystic kidney disease (PKD). Asparagine synthetase drives glutamine utilization in this disease and it is upregulated in human and mouse tissues. Its inhibition retards disease progression and rescues metabolic derangement in PKD mice. Glutamine utilization and cyst expansion are driven by ASNS upregulation in PKD. PKD cystic phenotype and metabolic rewiring are hampered by Asns-ASO. Glutaminolysis, pyrimidine biosynthesis and proliferation are driven by a GCN2-ATF4-ASNS axis. PKD is further delayed by co-targeting glutaminolysis and glycolysis with Asns-ASO and 2DG.