Role of PFKFB3-driven glycolysis in sepsis

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 MESSAGE Sepsis 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.

Automated summary

Sepsis is the leading cause of infection-related death, and metabolic disorder, particularly intensified glycolysis, plays a vital role in the progression of sepsis. The enzyme PFKFB3 controls the rate of glycolysis and has been found to be accelerated by sepsis in various cells, leading to excessive inflammation and mortality. Inhibiting PFKFB3 alone or in combination shows promising potential for sepsis treatment. This review summarizes the role of PFKFB3-driven glycolysis in immunocyte activation and nonimmune cell damage in sepsis, as well as recent advancements in PFKFB3 drugs and their therapeutic application in sepsis.