Pyruvate Kinase M2 Nuclear Translocation Regulate Ferroptosis-Associated Acute Lung Injury in Cytokine Storm

Cytokine storm (CS) is associated with macrophage dysfunction and acute lung injury (ALI), both of which can contribute to increased patient mortality. Pro-inflammatory macrophages preferentially rely on glycolysis, with pyruvate kinase M2 (PKM2) playing a pivotal role as a key enzyme. The connection between CS and ALI involves cell death, with ferroptosis—a recently identified form of programmed cell death—being implicated. However, the interplay between glycolysis and ferroptosis in the context of CS-induced ALI remains poorly understood. In models of CS-associated ALI induced by poly I:C (10 mg/kg, i.v.) and LPS (5 mg/kg, i.p.) (IC: LPS), significant ferroptosis is observed. Treatment with Ferrostatin-1 (a ferroptosis inhibitor) reduces both mortality and lung injury in the IC:LPS model. Additionally, alveolar macrophages (AMs) from this model show enhanced glycolysis and PKM2 translocation. Administration of ML-265, a PKM2 monomer/dimer inhibitor, promotes the formation of a highly active tetrameric PKM2, improving survival and mitigating ALI. ML-265 treatment also reduces ferroptosis and restores the balance between anaerobic glycolysis and oxidative phosphorylation. Notably, in patients with lung infections, the intracellular levels of PKM2 correlate with circulating inflammation. Enhanced ferroptosis and PKM2 nuclear translocation are observed in CD14+ blood monocytes from lung infection ML265 patients experiencing CS. In conclusion, PKM2 serves as a critical regulatory node that integrates metabolic reprogramming with nuclear function to regulate ferroptosis. Targeting PKM2 may offer a potential strategy to prevent or alleviate the hyper-inflammatory state and cytokine storm syndrome, particularly by modulating aberrant ferroptotic cell death.