Fatigue is a subjective discomfort,often manifested in a variety of physical and mental complaints.It can not only develop into an independent disease,but also is a symptom of a variety of diseases,seriously reducing people's quality of life.The pathogenesis of fatigue is complex.In recent years,the changes of central and peripheral neurotransmitter levels and abnormal energy metabolism are considered to be the main causes.Purine substances such as adenosine triphosphate (ATP) are mainly involved in the process of somatic energy demand in cells,and as important signal molecules,they participate in effective neurotransmission,neuron-glial interaction,immune response and control outside cells.They have attracted extensive attention in fatigue research.Extracellular ATP metabolism further activates P1 and P2 receptors in a concentration dependent manner,while ecto-nucleotidases control the concentration of purine substances by releasing receptor ligands to terminate or promote purine signaling pathway.This paper summarizes the synergistic effects of purinergic signaling and ecto-nucleotidases on the perception and development of fatigue,so as to provide a basis for further research on the pathogenesis and effective treatment of fatigue.