Department of Critical Care Medicine, Affiliated Jinling Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
Department of Critical Care Medicine, Affiliated Jinling Hospital of Nanjing University, Nanjing, China.
Ann Med. 2023 Dec;55(1):1278-1289. doi: 10.1080/07853890.2023.2191217.
Sepsis is still the leading cause of death as a result of infection. Metabolic disorder plays a vital role in sepsis progression. Glycolysis intensification is the most characteristic feature of sepsis-related metabolic disorders. The enzyme 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3) is a critical engine that controls the rate of glycolysis. Recent studies have revealed that sepsis accelerates the rate of PFKFB3-driven glycolysis in different cells, including macrophages, neutrophils, endothelial cells and lung fibroblasts. Furthermore, increased PFKFB3 is closely related to the excessive inflammatory response and high mortality in sepsis. Interestingly, inhibition of PFKFB3 alone or in combination has also shown great potential in the treatment of sepsis. Therefore, an improved understanding of the canonical and noncanonical functions of PFKFB3 may provide a novel combinatorial therapeutic target for sepsis. This review summarizes the role of PFKFB3-driven glycolysis in the regulation of immunocyte activation and nonimmune cell damage in sepsis. In addition, we present recent achievements in the development of PFKFB3 drugs and discuss their potential therapeutic roles in sepsis.KEY MESSAGESepsis induces high expression of PFKFB3 in immunocytes and nonimmune cells, thereby enhancing cellular glycolytic flux.PFKFB3-driven glycolysis reprogramming is closely related to an excessive inflammatory response and high mortality in sepsis.Inhibition of PFKFB3 alone or in combination provides a novel combinatorial therapeutic target for sepsis.
败血症仍然是感染导致死亡的主要原因。代谢紊乱在败血症的进展中起着至关重要的作用。糖酵解的加强是败血症相关代谢紊乱的最典型特征。酶 6-磷酸果糖-2-激酶/果糖-2,6-二磷酸酶 3（PFKFB3）是控制糖酵解速度的关键引擎。最近的研究表明，败血症会加速不同细胞（包括巨噬细胞、中性粒细胞、内皮细胞和肺成纤维细胞）中 PFKFB3 驱动的糖酵解速度。此外，PFKFB3 的增加与败血症中过度的炎症反应和高死亡率密切相关。有趣的是，单独或联合抑制 PFKFB3 在败血症治疗中也显示出巨大的潜力。因此，深入了解 PFKFB3 的典型和非典型功能可能为败血症提供新的联合治疗靶点。本综述总结了 PFKFB3 驱动的糖酵解在败血症中免疫细胞激活和非免疫细胞损伤调节中的作用。此外，我们还介绍了 PFKFB3 药物研发的最新进展，并讨论了它们在败血症中的潜在治疗作用。关键信息败血症诱导免疫细胞和非免疫细胞中 PFKFB3 的高表达，从而增强细胞的糖酵解通量。PFKFB3 驱动的糖酵解重编程与败血症中过度的炎症反应和高死亡率密切相关。单独或联合抑制 PFKFB3 为败血症提供了新的联合治疗靶点。
