ECM1 is a secreted extracellular matrix protein with multiple roles in tissue homeostasis and disease prevention. Its primary function involves negative regulation of bone mineralization and suppression of fibrotic pathways. Mechanistically, ECM1 stabilizes inactive transforming growth factor β (TGF-β) by interacting with αv integrins and binding latent TGF-β activators such as thrombospondins and ADAMTS proteases, preventing hepatic stellate cell activation 12. Additionally, ECM1 inhibits matrix metalloproteinase-9 proteolytic activity and promotes endothelial cell proliferation and angiogenesis. ECM1 also modulates iron homeostasis through interaction with PCBP1 to mitigate lipid peroxidation and supports M1 macrophage polarization via the GM-CSF/STAT5 pathway 34. Pathogenic loss-of-function mutations in ECM1 cause lipoid proteinosis, a rare autosomal recessive disorder characterized by hyaline material deposition in skin and mucous membranes, with prominent neuropsychiatric manifestations including amygdala calcifications and temporal lobe epilepsy 5. At the tissue level, ECM1 deficiency accelerates hepatic fibrosis and metabolic dysfunction-associated steatotic liver disease progression 13. Conversely, in bone metastatic prostate cancer, osteoblast-derived ECM1 promotes acquired resistance to the androgen receptor antagonist enzalutamide through ENO1-MAPK signaling activation 6. A genome-wide association study identified ECM1 variants as contributing to aging risk in population-based cohorts 7. Clinical therapeutic development targeting ECM1 restoration or its representative peptides may benefit patients with hepatic fibrosis and metabolic liver disease.