Enolase-1 and Inflammation

Enolase-1 (ENO-1) is classically known as a highly conserved glycolytic enzyme that catalyzes the conversion of 2-phosphoglycerate to phosphoenolpyruvate in the final steps of glycolysis. This enzyme, however, is being increasingly implicated as a multifunctional moonlighting protein with compartment-specific roles in inflammation. Within the cytosol, ENO-1 regulates macrophage inflammation during sepsis; on the cell surface, it functions as a plasminogen receptor, and extracellularly, it can participate in innate immune signaling. Across innate and adaptive immunity, ENO-1 has been implicated in macrophage activation, neutrophil recruitment, endothelial cell dysfunction, fibroblast remodeling, and autoantigenicity. These functions have been linked to sepsis, acute respiratory distress syndrome, acute organ injury, hemorrhagic shock, rheumatoid arthritis, and cancer-associated inflammation in the tumor microenvironment. Therapeutic targeting of ENO-1 includes small-molecule inhibitors and monoclonal antibodies. ENO-1, with its compartment-specific functions in disease pathogenesis, serves as a significant therapeutic target for inflammatory diseases. In this review, we discuss the novel compartment-specific roles of ENO-1 in inflammatory diseases, defining its functions beyond its role in glycolysis. We conclude that both the metabolic and moonlighting functions of ENO-1 contribute to inflammation, and future studies should delineate its compartment-specific roles in inflammatory pathophysiology, as compartment-specific targeting may represent the future of ENO-1-directed therapy.