Given the rapid development in precision medicine,tremendous efforts have been devoted to discovering new biomarkers for disease diagnosis and treatment.Esophageal cancer-related gene-4 (ECRG4),which is initially known as a new candidate tumor suppressor gene,is emerging as a sentinel molecule for gauging tissue homeostasis.ECRG4 is unique in its cytokine-like functional patte and epigenetically-regulated gene expression patte.The gene can be released from the cell membrane upon activation and detected in liquid biopsy,thus offering considerable potential in precision medicine.This review provides an updated summary on the biology of ECRG4,with emphasis on its important roles in cancer diagnosis and therapy.The future perspectives of ECRG4 as a potential molecular marker in precision medicine are also discussed in detail.