Cytokine storm (CS) is linked with macrophage dysfunction and acute lung injury (ALI), which can lead to patient mortality. Glycolysis is preferentially exploited by the pro-inflammatory macrophages, in which pyruvate kinase M2 (PKM2) is a critical enzyme. The mechanism underlying the link between CS and ALI involves cell death, with the recently discovered programmed cell death known as ferroptosis being involved. However, the relationship between the glycolysis and ferroptosis in the context of CS-related ALI remains unclear. CS-associated ALI induced by poly I:C (10 mg/kg, i.v) and LPS (5 mg/kg, i.p) (IC: LPS) exhibit significant ferroptosis. Ferrostatin-1 (ferroptosis inhibitor) treatment attenuated IC:LPS‑induced mortality and lung injury. Moreover, Alveolar macrophage (AM) from IC:LPS model exhibited enhanced glycolysis and PKM2 translocation. The administration of ML-265(PKM2 monomer/dimer inhibitor) resulted in the formation of a highly active tetrameric PKM2, leading to improved survival and attenuation of ALI. Furthermore, ML-265 treatment decreased ferroptosis and restored the balance between anaerobic glycolysis and oxidative phosphorylation. Notably, in patients with lung infection, intracellular expression level of PKM2 were correlated with circulating inflammation. Enhanced ferroptosis and PKM2 nuclear translocation was noticed in CD14⁺ blood monocytes of lung infection patients with CS. In conclusion, PKM2 is a key regulatory node integrating metabolic reprograming with intra-nuclear function for the regulation of ferroptosis. Targeting PKM2 could be explored as a potential means in the future to prevent or alleviate hyper-inflammatory state or cytokines storm syndrome with aberrant ferroptotic cell death.

细胞因子风暴 (CS) 与巨噬细胞功能障碍和急性肺损伤 (ALI) 有关，可导致患者死亡。糖酵解优先被促炎巨噬细胞利用，其中丙酮酸激酶 M2 (PKM2) 是一种关键酶。CS 和 ALI 之间联系的潜在机制涉及细胞死亡，其中涉及最近发现的称为铁死亡的程序性细胞死亡。然而，CS 相关 ALI 中糖酵解和铁死亡之间的关系仍不清楚。由 Poly I:C（10 mg/kg，静脉注射）和 LPS（5 mg/kg，腹腔注射）（IC：LPS）诱导的 CS 相关 ALI 表现出显着的铁死亡。Ferrostatin-1（铁死亡抑制剂）治疗可减轻 IC:LPS 引起的死亡率和肺损伤。此外，IC:LPS 模型中的肺泡巨噬细胞 (AM) 表现出增强的糖酵解和 PKM2 易位。ML-265（PKM2 单体/二聚体抑制剂）的施用导致高活性四聚体 PKM2 的形成，从而提高了 ALI 的存活率并减轻了病情。此外，ML-265 治疗可减少铁死亡并恢复无氧糖酵解和氧化磷酸化之间的平衡。值得注意的是，在肺部感染患者中，PKM2 的细胞内表达水平与循环炎症相关。^{在患有 CS 的肺部感染患者的 CD14 +}血单核细胞中观察到增强的铁死亡和 PKM2 核易位。总之，PKM2是整合代谢重编程和核内功能来调节铁死亡的关键调节节点。未来可以探索靶向 PKM2 作为预防或减轻高炎症状态或伴有异常铁死亡细胞死亡的细胞因子风暴综合征的潜在手段。