{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T15:57:13Z","timestamp":1791907033963,"version":"4.3.4"},"reference-count":204,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2019,3,20]],"date-time":"2019-03-20T00:00:00Z","timestamp":1553040000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004329","name":"Javna Agencija za Raziskovalno Dejavnost RS","doi-asserted-by":"publisher","award":["P1-0140"],"award-info":[{"award-number":["P1-0140"]}],"id":[{"id":"10.13039\/501100004329","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001688","name":"International Centre for Genetic Engineering and Biotechnology","doi-asserted-by":"publisher","award":["CRP\/SVN 16-01"],"award-info":[{"award-number":["CRP\/SVN 16-01"]}],"id":[{"id":"10.13039\/501100001688","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>For a long time, cysteine cathepsins were considered primarily as proteases crucial for nonspecific bulk proteolysis in the endolysosomal system. However, this view has dramatically changed, and cathepsins are now considered key players in many important physiological processes, including in diseases like cancer, rheumatoid arthritis, and various inflammatory diseases. Cathepsins are emerging as important players in the extracellular space, and the paradigm is shifting from the degrading enzymes to the enzymes that can also specifically modify extracellular proteins. In pathological conditions, the activity of cathepsins is often dysregulated, resulting in their overexpression and secretion into the extracellular space. This is typically observed in cancer and inflammation, and cathepsins are therefore considered valuable diagnostic and therapeutic targets. In particular, the investigation of limited proteolysis by cathepsins in the extracellular space is opening numerous possibilities for future break-through discoveries. In this review, we highlight the most important findings that establish cysteine cathepsins as important players in the extracellular space and discuss their roles that reach beyond processing and degradation of extracellular matrix (ECM) components. In addition, we discuss the recent developments in cathepsin research and the new possibilities that are opening in translational medicine.<\/jats:p>","DOI":"10.3390\/cells8030264","type":"journal-article","created":{"date-parts":[[2019,3,21]],"date-time":"2019-03-21T04:11:56Z","timestamp":1553141516000},"page":"264","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":399,"title":["Cysteine Cathepsins and Their Extracellular Roles: Shaping the Microenvironment"],"prefix":"10.3390","volume":"8","author":[{"given":"Eva","family":"Vidak","sequence":"first","affiliation":[{"name":"Jozef Stefan Institute, Department of Biochemistry and Molecular and Structural Biology, Jamova 39, SI-1000 Ljubljana, Slovenia"},{"name":"International Postgraduate School Jozef Stefan, Jamova 39, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Urban","family":"Javor\u0161ek","sequence":"additional","affiliation":[{"name":"Jozef Stefan Institute, Department of Biochemistry and Molecular and Structural Biology, Jamova 39, SI-1000 Ljubljana, Slovenia"},{"name":"International Postgraduate School Jozef Stefan, Jamova 39, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matej","family":"Vizovi\u0161ek","sequence":"additional","affiliation":[{"name":"Jozef Stefan Institute, Department of Biochemistry and Molecular and Structural Biology, Jamova 39, SI-1000 Ljubljana, Slovenia"},{"name":"Department of Biology, Institute of Molecular Systems Biology, ETH Z\u00fcrich Otto-Stern-Weg 3, 8093 Z\u00fcrich, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9007-5764","authenticated-orcid":false,"given":"Boris","family":"Turk","sequence":"additional","affiliation":[{"name":"Jozef Stefan Institute, Department of Biochemistry and Molecular and Structural Biology, Jamova 39, SI-1000 Ljubljana, Slovenia"},{"name":"Faculty of Chemistry and Chemical Technology, University of Ljubljana, Vecna pot 113, SI-1000 Ljubljana, Slovenia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,3,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"68","DOI":"10.1016\/j.bbapap.2011.10.002","article-title":"Cysteine cathepsins: From structure, function and regulation to new frontiers","volume":"1824","author":"Turk","year":"2012","journal-title":"Biochim. 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