MMP12 (matrix metallopeptidase 12) is an elastolytic endopeptidase predominantly produced by macrophages with broad roles in tissue remodeling and extracellular matrix (ECM) degradation. MMP12 preferentially cleaves elastin and collagen, accepting large and small amino acids at the P1' site with preference for leucine [UniProt]. Functionally, MMP12 catalyzes both elastin and collagen catabolism while regulating macrophage phenotypes and cellular transitions. Mechanistically, MMP12 expression is regulated by Th2 cytokines (IL-4, IL-13) and histamine in M2 macrophages, particularly in inflammatory contexts 1. Beyond proteolysis, MMP12 promotes pathogenic macrophage-to-myofibroblast transition (MMT) through TGFβ signaling in fibrotic diseases 23. MMP12-generated elastin fragments can function as self-antigens, driving autoimmune responses in cigarette smoke-exposed lungs 4. Clinically, elevated MMP12 expression associates with poor prognosis across multiple cancers 5 and contributes to fibrotic diseases including subretinal fibrosis in age-related macular degeneration 2, intervertebral disc degeneration 3, and endometriosis-associated fibrosis 6. MMP12-expressing macrophages are pathogenic in hepatic and pulmonary fibrosis 74. Conversely, MMP12 modulation shows therapeutic potential, with MMP12 inhibition reducing fibrosis and improving outcomes in preclinical models 23.