show Abstracthide AbstractPersistently elevated glycolysis in kidney has been demonstrated to promote chronic kidney disease. However, the underlying mechanism remains largely unclear. Here, we observed that PFKFB3, a key glycolytic enzyme, was remarkably induced in kidney proximal tubular cells following ischemia-reperfusion injury in mice, as well as in multiple etiologies of chronic kidney disease patients. PFKFB3 expression was positively correlated with the severity of renal fibrosis. Proximal tubular epithelial-specific deletion of PFKFB3 significantly reduced renal lactate levels, mitigated inflammation and fibrosis, and preserved renal function in the IRI mouse model. Targeting PFKFB3-mediated inflammation activation in tubular cells could be a novel strategy for chronic kidney disease therapy.