{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T08:37:30Z","timestamp":1773995850957,"version":"3.50.1"},"reference-count":94,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T00:00:00Z","timestamp":1773964800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>To systematically review the pleiotropic roles of Cathepsin K (CTSK) beyond classical bone resorption, elucidating its critical function in regulating extracellular matrix (ECM) dynamics and epithelial-mesenchymal transition (EMT) across diverse pathological systems.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>A comprehensive analysis was conducted to synthesize the molecular architecture and signaling networks of CTSK, including the RANKL-RANK and NF-\u03baB pathways. The review stratifies mechanistic and clinical evidence across five major domains: malignant tumors, cardiovascular diseases, pulmonary disorders, orthopedic conditions, and metabolic diseases, while evaluating the development and risks of CTSK inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>CTSK acts as a versatile protease in ECM remodeling. In oncology, it facilitates metastasis in breast, gastric, and prostate cancers by degrading matrix barriers and activating EMT. In cardiovascular and pulmonary pathologies, CTSK exhibits a dualistic nature: it promotes atherosclerotic plaque instability and fibrosis progression but is protective in ischemic vascular remodeling. Furthermore, in metabolic disorders like T2DM and obesity, upregulated CTSK drives pathological collagen degradation, compromising tissue integrity. In orthopedic diseases, it is a key effector molecule responsible for bone matrix degradation and impaired tissue repair. Therapies targeting CTSK (such as inhibitors) show promise but raise safety concerns including off-target effects and increased stroke risk.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>CTSK is a central hub integrating upstream signals to regulate systemic ECM homeostasis, making it a promising therapeutic target. Future therapeutic strategies should focus on developing highly selective inhibitors to achieve precise regulation and balance efficacy with safety.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fonc.2026.1761157","type":"journal-article","created":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T05:23:28Z","timestamp":1773984208000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Relationship between cathepsin K and extracellular matrix dynamics: a comprehensive review"],"prefix":"10.3389","volume":"16","author":[{"given":"Guodong","family":"Zang","sequence":"first","affiliation":[{"name":"Respiratory and Critical Care Medicine Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine","place":["Jinan, Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tingting","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Hepatology, Shandong Provincial Third Hospital, Shandong University","place":["Jinan Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hao","family":"Tian","sequence":"additional","affiliation":[{"name":"Respiratory and Critical Care Medicine Department, Linyi Hospital of Traditional Chinese Medicine","place":["Linyi, Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yijie","family":"Wang","sequence":"additional","affiliation":[{"name":"The First Clinical Medical College, Shandong University of Traditional Chinese Medicine","place":["Jinan, Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dengru","family":"Jia","sequence":"additional","affiliation":[{"name":"Graduate School, Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rui","family":"Fan","sequence":"additional","affiliation":[{"name":"Respiratory and Critical Care Medicine Department, Provincial Hospital Affiliated to Shandong First Medical University","place":["Jinan, Shandong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,3,20]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.21.12511","article-title":"Cathepsin K, but not cathepsins B, L, or S, is abundantly expressed in human osteoclasts","volume":"271","author":"Drake","year":"1996","journal-title":"J Biol Chem"},{"key":"B2","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1186\/s13104-015-1284-8","article-title":"Matrix-metalloproteinase-9 is cleaved and activated by cathepsin K","volume":"8","author":"Christensen","year":"2015","journal-title":"BMC Res Notes"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.48.32347","article-title":"The collagenolytic activity of cathepsin K is unique among mammalian proteinases","volume":"273","author":"Garnero","year":"1998","journal-title":"J Biol Chem"},{"key":"B4","doi-asserted-by":"publisher","first-page":"5963","DOI":"10.3390\/curroncol29080471","article-title":"Cathepsin K: A versatile potential biomarker and therapeutic target for various cancers","volume":"29","author":"Qian","year":"2022","journal-title":"Curr Oncol"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1359\/jbmr.1999.14.10.1654","article-title":"Cathepsin K knockout mice develop osteopetrosis due to a deficit in matrix degradation but not demineralization","volume":"14","author":"Gowen","year":"1999","journal-title":"J Bone Miner Res"},{"key":"B6","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1111\/j.1468-3083.2010.03743.x","article-title":"Stromal expression of cathepsin K in squamous cell carcinoma","volume":"25","author":"Yan","year":"2011","journal-title":"J Eur Acad Dermatol Venereol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1080\/08820139.2025.2569768","article-title":"Ctsk) in inflammatory and immune-mediated diseases","volume":"55","author":"Lin","year":"2025","journal-title":"Immunol Invest"},{"key":"B8","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/0014-5793(94)01349-6","article-title":"Molecular cloning of human cathepsin O, a novel endoproteinase and homologue of rabbit oc2","volume":"357","author":"Shi","year":"1995","journal-title":"FEBS Lett"},{"key":"B9","doi-asserted-by":"publisher","first-page":"9920","DOI":"10.1074\/jbc.M116.719054","article-title":"Cathepsin S contributes to the pathogenesis of muscular dystrophy in mice","volume":"291","author":"Tjondrokoesoemo","year":"2016","journal-title":"J Biol Chem"},{"key":"B10","doi-asserted-by":"publisher","first-page":"1621","DOI":"10.1172\/jci113497","article-title":"Complete nucleotide and deduced amino acid sequences of human and murine preprocathepsin L. 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