LGMN (legumain) is a lysosomal cysteine protease with strict specificity for asparaginyl bond hydrolysis, and can slowly cleave aspartyl bonds under acidic conditions 1. It functions primarily in antigen processing and presentation for MHC class II and class I pathways, facilitating Perforin-2 maturation in cross-presenting dendritic cells 2. Beyond antigen presentation, LGMN plays critical roles in tissue homeostasis and disease pathology. In cardiac repair after myocardial infarction, macrophage-derived LGMN promotes clearance and degradation of apoptotic cardiomyocytes through enhanced phagolysosomal cargo degradation, supporting inflammation resolution and functional recovery 34. In acute kidney injury, LGMN facilitates chaperone-mediated autophagy of glutathione peroxidase 4, promoting tubular ferroptosis 5. Conversely, LGMN promotes pathological vascular remodeling in thoracic aortic dissection by binding integrin αvβ3 on vascular smooth muscle cells, blocking Rho GTPase activation and promoting phenotypic switching 6. In immunopathology, CD4+ T cell LGMN deficiency attenuates hypertension by preserving TRAF6-mediated regulatory T cell differentiation and function 7. In glioblastoma, TAM-derived LGMN drives immunosuppression through dual mechanisms: promoting macrophage infiltration via GSK3β/STAT3 signaling and activating integrin αv/AKT/p65 in tumor cells 89. LGMN emerges as a therapeutic target across fibrotic, cardiovascular, and malignant diseases.