{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T06:01:54Z","timestamp":1772517714458,"version":"3.50.1"},"reference-count":90,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,2,28]],"date-time":"2026-02-28T00:00:00Z","timestamp":1772236800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Claire and Amedee Maratier Institute Grant for the Study of Blindness and Visual Disorders, Faculty of Medicine, Tel Aviv University"},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01HL142975"],"award-info":[{"award-number":["R01HL142975"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"United States\u2014Israel Binational Science Foundation","award":["2021191"],"award-info":[{"award-number":["2021191"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Protein C (PC) and its activated form, activated protein C (APC), are well-established regulators of coagulation and cytoprotection. While their systemic functions are extensively characterized, their physiological roles in the retina have only recently begun to be explored. This gap persists despite the observation that congenital PC deficiency is consistently associated with severe ocular complications. Emerging evidence, including the development of a murine model of severe protein C deficiency (SPCD), indicates that APC contributes to retinal integrity and vascular homeostasis under physiological conditions. Beyond its physiological function, APC has shown therapeutic activity in several models of retinal disease. Recent findings from our group further demonstrated that intravenously administered APC and its cytoprotective analog, 3K3A-APC, can cross the blood\u2013retina barrier via the endothelial protein C receptor (EPCR), despite their relatively large molecular weight (~62 kDa), and induce cytoprotective activities in the retina. These findings highlight the translational potential of 3K3A-APC and support its further development as a systemically delivered therapeutic approach for retinal pathologies. This review integrates current knowledge of the molecular biology of the PC\/APC pathways with its emerging physiological functions in the retina, and the accumulating preclinical and early clinical evidence that supports its therapeutic relevance.<\/jats:p>","DOI":"10.3390\/ijms27052282","type":"journal-article","created":{"date-parts":[[2026,3,2]],"date-time":"2026-03-02T10:24:34Z","timestamp":1772447074000},"page":"2282","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Activated Protein C and the Retina: From Physiology to Therapeutic Potential"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9451-5253","authenticated-orcid":false,"given":"Alon","family":"Zahavi","sequence":"first","affiliation":[{"name":"Ophthalmology Department and Laboratory of Eye Research, Felsenstein Medical Research Center, Rabin Medical Center, Petah-Tikva 4941492, Israel"},{"name":"Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3971-0336","authenticated-orcid":false,"given":"Sarina","family":"Levy-Mendelovich","sequence":"additional","affiliation":[{"name":"The Amalia Biron Research Institute of Thrombosis & Hemostasis, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"National Hemophilia Center, Thrombosis & Hemostasis Institute, Sheba Medical Center, Ramat Gan 52621, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"John H.","family":"Griffin","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, The Scripps Research Institute, La Jolla, CA 92037, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1279-2557","authenticated-orcid":false,"given":"Tami","family":"Livnat","sequence":"additional","affiliation":[{"name":"The Amalia Biron Research Institute of Thrombosis & Hemostasis, Gray Faculty of Medical & Health Sciences, Tel Aviv University, Tel Aviv 6997801, Israel"},{"name":"National Hemophilia Center, Thrombosis & Hemostasis Institute, Sheba Medical Center, Ramat Gan 52621, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,28]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"3","DOI":"10.5301\/EJO.2010.6049","article-title":"Blood-Retinal Barrier","volume":"21","author":"Bernardes","year":"2011","journal-title":"Eur. 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