{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T03:30:30Z","timestamp":1790998230839,"version":"4.1.0"},"reference-count":44,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2026,5,20]],"date-time":"2026-05-20T00:00:00Z","timestamp":1779235200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Plasminogen activator inhibitor-1 (PAI-1), encoded by SERPINE1, is the principal physiological inhibitor of tissue-type and urokinase-type plasminogen activators and a central regulator of fibrinolysis. Beyond its canonical hemostatic role, PAI-1 has emerged as a pleiotropic mediator of tissue remodeling, fibrosis, metabolic dysfunction, cancer progression, cellular senescence, and age-associated immune dysregulation. A central argument of this review is that PAI-1 should be understood not only as a downstream biomarker of aging-associated pathology, but also as an active effector linking senescence-associated secretory phenotype (SASP) signaling, chronic low-grade inflammation, impaired immune surveillance, fibrotic extracellular matrix remodeling, and a prothrombotic state. In this framework, PAI-1 may function as an immune-aging checkpoint: a molecular node through which senescent, stromal, malignant, and inflammatory cells reinforce immune evasion and tissue dysfunction. Structure-guided drug discovery has enabled the development of small-molecule PAI-1 inhibitors, including TM5275, TM5441, TM5509, and TM5614. Among these, TM5614 is an orally available investigational compound that has progressed to clinical evaluation. Preclinical studies support anti-thrombotic, anti-fibrotic, anti-inflammatory, anti-senescent, and tumor-microenvironment-modulating effects of PAI-1 inhibition, while early clinical studies have evaluated TM5614 in chronic myeloid leukemia, immune-checkpoint-refractory malignant melanoma, non-small-cell lung cancer, and COVID-19-associated pneumonia. This review summarizes the biology of PAI-1, expands the discussion of immunoaging, reviews representative preclinical and clinical data, compares available PAI-1 inhibitors, and discusses the translational opportunities and safety considerations for TM5614 and related compounds.<\/jats:p>","DOI":"10.3390\/cells15100941","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T08:06:26Z","timestamp":1779696386000},"page":"941","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Plasminogen Activator Inhibitor-1 as a Therapeutic Target for Healthy Longevity, Immunosenescence, and Age-Related Disease: Translational Development of the Small-Molecule Inhibitor TM5614"],"prefix":"10.3390","volume":"15","author":[{"given":"Mohamed","family":"Abdelhakim","sequence":"first","affiliation":[{"name":"Department of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshio","family":"Miyata","sequence":"additional","affiliation":[{"name":"Department of Molecular Medicine and Therapy, Tohoku University Graduate School of Medicine, 2-1 Seiryo-machi, Aoba-ku, Sendai 980-8575, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2956","DOI":"10.1073\/pnas.80.10.2956","article-title":"Detection of an unusually stable fibrinolytic inhibitor produced by bovine endothelial cells","volume":"80","author":"Loskutoff","year":"1983","journal-title":"Proc. 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