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Despite decades of studies into the mechanisms underlying acute kidney injury (AKI), the effective clinical therapies are still limited. Here we report that the development of AKI was attenuated by conditional knockout of phosphoglycerate kinase 1 (PGK1) in renal tubular epithelial cells (RTECs) and aggravated by specific overexpression of PGK1 and administration of 3-phosphoglycerate (3-PG) in male mice. PGK1 interacted with pyruvate kinase M2 (PKM2), inducing PKM2 phosphorylation, promoting the formation of the PKM2 dimer and the subsequent nuclear translocation of PKM2. In the nucleus, the interaction of PKM2 with Pknox1 potentiated the enrichment of Pknox1 within ALOX12 promoters, which resulted in ALOX12-mediated ferroptosis in RTECs. Our drug screening experiments identified L7DG as a potential PGK1 inhibitor which exhibited protective effects against ischemic/reperfusion (I/R)-induced renal injury. Overall, we establish that genetic and pharmacological inhibition of PGK1 might be proposed as an avenue for managing AKI.