{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,15]],"date-time":"2026-10-15T17:46:39Z","timestamp":1792086399020,"version":"4.4.0"},"reference-count":156,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2026,2,7]],"date-time":"2026-02-07T00:00:00Z","timestamp":1770422400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"NIH R01","doi-asserted-by":"publisher","award":["EY024710"],"award-info":[{"award-number":["EY024710"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"NIH R01","doi-asserted-by":"publisher","award":["EY029426"],"award-info":[{"award-number":["EY029426"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"NIH R01","doi-asserted-by":"publisher","award":["EY036253"],"award-info":[{"award-number":["EY036253"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"NIH R01","doi-asserted-by":"publisher","award":["EY033622"],"award-info":[{"award-number":["EY033622"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000053","name":"NIH R01","doi-asserted-by":"publisher","award":["EY001792"],"award-info":[{"award-number":["EY001792"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pathogens"],"abstract":"<jats:p>Herpes simplex keratitis (HSK) is classically described as an immunopathological disease driven by recurrent herpes simplex virus type 1 (HSV-1) infection and chronic inflammation. So far, immune-mediated tissue damage has not fully explained the molecular mechanisms governing disease progression toward corneal neovascularization (CNV), a major cause of corneal blindness and vision loss worldwide. Increasing evidence indicates that CNV results from complex interactions that extend beyond leukocyte-driven inflammation, as the host cell machinery, including key pathways and molecular markers, is hijacked by the invading virus to establish and perpetuate replication and lifelong latency. These host\u2013cell interactions regulate angiogenic imbalance, vascular privilege, and tissue remodeling, which collectively promote pathological vascular invasion. This review re-examines HSK by focusing on molecular mechanistic pathways and drivers that regulate disease progression towards CNV, upstream of immune response drivers. Specifically, we discuss the roles of endothelial growth factors, matrix metalloproteinases, Heparanase, and Syndecan-1 signaling, as well as microRNA-mediated regulation, and key signaling axes, including JAK2\/STAT3, PI3K\/AKT\/mTOR, and hypoxia signaling. By integrating these pathways and molecular markers, we propose an updated mechanistic framework, including a conceptual model for the underexplored role of heparanase, and identify pathway-level targets with potential therapeutic relevance for HSK-associated CNV.<\/jats:p>","DOI":"10.3390\/pathogens15020186","type":"journal-article","created":{"date-parts":[[2026,2,9]],"date-time":"2026-02-09T09:41:02Z","timestamp":1770630062000},"page":"186","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":5,"title":["Molecular Pathways Driving Corneal Neovascularization in Herpes Simplex Keratitis"],"prefix":"10.3390","volume":"15","author":[{"given":"Soromidayo","family":"Akinsiku","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Science, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3039-6953","authenticated-orcid":false,"given":"Deepak","family":"Shukla","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Science, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"},{"name":"Department of Microbiology and Immunology, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,7]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"315","DOI":"10.2471\/BLT.19.237149","article-title":"Herpes simplex virus: Global infection prevalence and incidence estimates, 2016","volume":"98","author":"James","year":"2020","journal-title":"Bull. 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