ENO1 functional plasticity linking metabolism with gene regulation and immunity at the host–pathogen interface

Enolase 1 (ENO1) is a highly conserved glycolytic enzyme that exhibits remarkable functional plasticity beyond its canonical metabolic role. Increasing evidence indicates that ENO1 participates in diverse cellular and host–pathogen processes, including metabolic adaptation, gene regulation, signaling, immune responses, and pathogen infection. Its functional output is not determined solely by its abundance but is shaped by cellular conditions and functional state, which are influenced by post-translational modifications, subcellular localization, molecular interactions, metabolic conditions, and extracellular or pathogen-derived stimuli. In this review, we summarize current evidence for the context-dependent functions of host ENO1 during infection, with particular emphasis on its roles in metabolic reprogramming, regulation of gene expression and pathogen replication, and modulation of host immunity and inflammation. We further discuss how pathogens can manipulate host ENO1 expression, stability, localization, or molecular interactions to facilitate infection, and distinguish these functions from those of pathogen-derived enolases, which contribute to microbial metabolism, invasion, and host interaction. By integrating these findings, we propose that ENO1 functions as a multifunctional regulatory hub, with its biological activities emerging from the specific molecular and cellular environments in which it operates. This framework provides a mechanistic perspective for understanding how a single conserved protein can engage distinct molecular partners and biological processes across different cellular and infectious settings, highlighting the functional versatility of ENO1 at the host–pathogen interface.