Up-regulation of a-enolase expression has been extensively reported for several types of cancer, including hepatocellular carcinoma, thyroid oncocytoma, lung and breast cancers among many others, and ENO1 gene expression is increased in 18 of 24 cancers classes analyzed. In some cases, overexpression of a-enolase positively correlated with tumor progression and clinical outcome. Additionally, altered levels of a-enolase were also found in Alzheimer’s disease, rheumatoid arthritis and systemic sclerosis. Alterations in a-enolase expression were also reported for flaviviruses’ infections. a-enolase is one of the up-regulated proteins in the midguts of Aedes aegypti mosquitoes and in the Aedes albopictus C6/36 cell line infected with different serotypes of DENV. Interestingly, a-enolase interacts with different viral proteins during the infection, including the capsid protein from DENV, envelope protein from WNV, NS3 protein from Kunjin virus and NS5 protein from Tick-borne encephalitis virus and from Alkhurma virus, although the biological relevance of these interactions remains unclear. Previously considered a cytoplasmic protein, a-enolase has also been identified in nucleus, plasma membrane, endosome, Golgi complex, peroxisome and in XL-184 extracellular exosome vesicles. It is noteworthy that enolase lacks signal sequences for any specific subcellular localization, and the molecular mechanisms involved in its membrane association as well as in its secretion are unknown. The subcellular localization of a-enolase is also modulated in different pathological states. For instance, LPS induces the translocation of a-enolase from cytoplasm to plasma membrane in monocytes. Also, an increase in a-enolase secretion has been observed in response to HIV-1 infection in macrophages and to DENV infection in hepatic cells, as reported here and in our previous study. Alterations in the secretion of a-enolase by liver cells could be involved not only in local effects, as cellular infiltration and hemorrhage reported in liver from patients who died from dengue, but also influence in systemic effects of dengue pathology such as plasma leakage and coagulopathies. Indeed, our preliminary results obtained with plasma samples from DENV-infected patients suggest an association between plasma levels of a-enolase and disease severity. These results point to a potential physiological role of a-enolase in dengue diseases. Another hypothesis for the role of a-enolase in dengue pathogenesis is that the increased amounts of extracellular, and possibly the membrane-associated, a-enolase would elicit humoral and cellular responses due to the production of autoantibodies and activation of T cells. Detection of anti-enolase antibodies has been reported for several inflammatory and autoimmune diseases, such as pancreatic cancer, lupus erythematosus, rheumatoid arthritis and inflammatory bowel disease. In addition, the presence of autoantibodies specifically to phosphorylated and citrullinated isoforms of a-enolase has been detected in serum from patients with pancreatic cancer and rheumatoid arthritis, respectively. Anti-enolase antibodies induced apoptosis in endothelial cells and production of inflammatory mediators.