Polo-like kinase 1 drives hypoxia-induced renal fibrosis via PTEN/PGK1-mediated glycolytic activation.

Renal fibrosis represents the common terminal pathological alteration in various chronic kidney diseases (CKD), with hypoxia driving its progression through aberrant activation of glycolysis. This study innovatively elucidates the molecular mechanism by which polo-like kinase 1 (PLK1) drives hypoxia-associated renal fibrosis through activating glycolysis. In mouse models of ischemia-reperfusion injury and hypoxia-treated HK-2 cell models, PLK1 expression was upregulated and correlated with extracellular matrix (ECM) deposition. Further investigation revealed that PLK1 phosphorylated phosphatase and tensin homolog (PTEN) at Ser380, suppressing its phosphatase activity and derepressing phosphoglycerate kinase 1 (PGK1). Liberated PGK1 underwent autophosphorylation at Tyr324, triggering glycolytic flux amplification and promoting ECM synthesis. Crucially, we identify PLK1 as a novel metabolic regulator in renal fibrosis, establishing a mechanistic link between PLK1-driven PTEN/PGK1 signaling and hypoxia-induced glycolytic reprogramming. The work identifies PGK1 Tyr324 autophosphorylation as a druggable target and demonstrates the therapeutic potential of clinical-stage PLK1 inhibitors for CKD. Targeting the PLK1/PTEN/PGK1 axis offers a dual therapeutic strategy to mitigate metabolic dysregulation and fibrosis, providing a transformative paradigm for CKD intervention.