{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMatrix metalloproteinase‐9 (MMP9) is a zinc‐dependent, multidomain endopeptidase that degrades numerous extracellular matrix proteins in a highly regulated manner. Detailed reviews have described its flexible structure, complex activation mechanisms, and broad substrate repertoire that underlie its various physiological and pathophysiological roles."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn vascular disease and tissue remodeling, MMP9 has emerged as a key mediator. Studies in abdominal aortic aneurysm models demonstrate that macrophage‐derived MMP9 is required for aortic wall degradation, as its absence prevents aneurysm formation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Similarly, elevated secretion of MMP9 by inflammatory cells contributes to atherosclerotic progression."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": " In ischemic stroke, tPA‐mediated upregulation of MMP9 disrupts blood–brain barrier integrity and exacerbates injury, while its altered activity is linked to hemorrhagic transformation and oxidative stress after ischemia."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of cancer metastasis and tumor progression, MMP9 facilitates local invasion, angiogenesis, and distant dissemination. Premetastatic lung endothelial induction of MMP9 via VEGFR‐1 signaling enhances lung metastasis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": ", and neutrophil‐derived, TIMP‐free proMMP9 is particularly potent in triggering angiogenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " MMP9 expression is transcriptionally upregulated and activated in gastric, ovarian, hepatocellular, and breast cancers, where it promotes epithelial–mesenchymal transition, extracellular matrix remodeling, and ascites formation."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "11", "end_ref": "16"}]}, {"type": "t", "text": " Moreover, microbial activation of MMP9 contributes to intestinal anastomotic leakage"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "17"}]}, {"type": "t", "text": ", while viral proteins such as HBx stimulate its expression to enhance invasiveness in hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "18"}]}, {"type": "t", "text": " In prostate cancer, MMP9 further facilitates the colonization of the bone microenvironment"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "19"}]}, {"type": "t", "text": "and supports angiogenic niches in the tumor stroma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMMP9 also exerts prominent roles in neural and inflammatory contexts. In neurodegeneration, astrocyte‐derived MMP9 participates in amyloid‐β clearance, thereby influencing Alzheimer’s disease pathology"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": ", while its focal expression at plaque margins is associated with demyelinating activity in multiple sclerosis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "22"}]}, {"type": "t", "text": " In addition, MMP9 modulates cell migration in non‐neural tissues; for example, IL‑8 stimulates trophoblast motility in part through increased MMP9 production."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "23"}]}, {"type": "t", "text": " In wounds such as diabetic ulcers, elevated MMP9 levels correlate with impaired healing"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "24"}]}, {"type": "t", "text": ", and in chronic obstructive pulmonary disease, oxidative stress–mediated upregulation of MMP9 contributes to tissue damage."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "25"}]}, {"type": "t", "text": " Studies with natural inhibitors like resveratrol further illustrate how modulation of MMP9 can ameliorate its deleterious effects."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "26"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nThe regulation of MMP9 activity is multifaceted. Its enzymatic stability is enhanced by binding to neutrophil gelatinase–associated lipocalin (NGAL), which protects MMP9 from autodegradation."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "27"}]}, {"type": "t", "text": " In hepatic injury, increased MMP9 activity promotes progenitor cell homing"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "29"}]}, {"type": "t", "text": ", and its secretion in endothelial‐derived vesicles supports angiogenic processes."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "30"}]}, {"type": "t", "text": " Transcription factors such as Runx2 help drive MMP9 expression in the context of bone metastasis"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "31"}]}, {"type": "t", "text": ", while RNA interference against MMP9 reduces invasion in glioma models."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "32"}]}, {"type": "t", "text": " MMP9 is also generated during ectodomain shedding events, as observed with RAGE"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "33"}]}, {"type": "t", "text": ", and its substrate repertoire has been expanded through degradomic approaches."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "34"}]}, {"type": "t", "text": " Moreover, dysregulated MMP9 expression contributes to autoimmunity"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "35"}]}, {"type": "t", "text": "and is induced by EGFR signaling via ERK and PI3K pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "36"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nGenetic variations and tissue‐specific regulatory processes further influence MMP9’s pathological impact. Polymorphism studies have implicated variations in metalloproteinase genes in smoking‐related lung injury and vascular remodeling"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "37"}]}, {"type": "t", "text": ", while aberrant MMP9 activity has been linked to metastatic spread in retinoblastoma."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "38"}]}, {"type": "t", "text": " In ovarian carcinoma, MMP9‐mediated E‑cadherin shedding disrupts cell–cell adhesion and promotes invasion"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "39"}]}, {"type": "t", "text": ", and M2‐polarized macrophages produce a TIMP‑free form of proMMP9 with high angiogenic potency."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "40"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nCollectively, these findings underscore the versatility of MMP9 as a central mediator of extracellular matrix degradation, cell migration, and angiogenesis across a broad spectrum of diseases—including cardiovascular disorders, multiple cancer types, neurodegenerative diseases, and chronic inflammatory conditions. Its complex regulation by proteolytic activation, binding partners, and intracellular signaling pathways makes it both a valuable biomarker and a promising target for therapeutic intervention.\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Griselda A Cabral-Pacheco, Idalia Garza-Veloz, Claudia Castruita-De la Rosa, et al. 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