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Earlier, we provide a proof-of-concept study identifying the regulation and the role of Cathepsin K (CTSK), a potent collagenase, in ECM homeostasis, actin bundling, and IOP regulation. Better understanding of the loss of CTSK function in TM remains unclear. Using siRNA-mediated knockdown of CTSK (siCTSK) in human TM cells, this study investigated the role of CTSK in actin and ECM homeostasis using an unbiased proteomics approach. Loss of CTSK significantly disrupted collagen biogenesis and ECM homeostasis. CTSK depletion also increased intracellular calcium levels, with proteomics data suggesting possible involvement of calcium-regulatory proteins. Additionally, PRKD1 activation enhanced actin polymerization through the LIMK1\/SSH1\/cofilin pathway, promoting focal adhesion maturation. Despite increased apoptotic markers (CASP3, CASP7, TRADD, PPM1F), caspase 3\/7 activation was not induced, suggesting apoptosis-independent cellular remodeling. Notably, RhoQ and myosin motor proteins were significantly downregulated, indicating altered mechanotransduction in TM cells. These findings highlight the role of CTSK in maintaining ECM homeostasis, calcium signaling, and cytoskeletal regulation in TM. Its depletion induces actin polymerization, which may influence aqueous humor outflow. Targeting CTSK-related pathways may provide novel therapeutic strategies for regulating IOP and preventing glaucoma progression.<\/jats:p>","DOI":"10.1101\/2025.02.10.637394","type":"posted-content","created":{"date-parts":[[2025,2,11]],"date-time":"2025-02-11T06:10:12Z","timestamp":1739254212000},"source":"Crossref","is-referenced-by-count":0,"title":["Loss of Cathepsin K impairs collagen biogenesis and enhances actin polymerization in trabecular meshwork"],"prefix":"10.64898","author":[{"given":"Avinash","family":"Soundararajan","sequence":"first","affiliation":[{"name":"Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krishna","family":"Jaysankar","sequence":"additional","affiliation":[{"name":"Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emma","family":"Doud","sequence":"additional","affiliation":[{"name":"Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rodahina Philihina","family":"Pasteurin","sequence":"additional","affiliation":[{"name":"Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States"},{"name":"Medical Neuroscience Graduate Program, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michelle","family":"Surma","sequence":"additional","affiliation":[{"name":"Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Padmanabhan P","family":"Pattabiraman","sequence":"additional","affiliation":[{"name":"Ophthalmology, Indiana University School of Medicine, Indianapolis, Indiana, United States"},{"name":"Medical Neuroscience Graduate Program, Stark Neuroscience Research Institute, Indiana University School of Medicine, Indianapolis, Indiana, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026041100434384000_2025.02.10.637394v1.1","doi-asserted-by":"publisher","DOI":"10.7189\/jogh.14.04252"},{"issue":"11","key":"2026041100434384000_2025.02.10.637394v1.2","first-page":"e11686","article-title":"Epidemiology of Glaucoma: The Past, Present, and Predictions for the Future","volume":"12","year":"2020","journal-title":"Cureus"},{"key":"2026041100434384000_2025.02.10.637394v1.3","doi-asserted-by":"publisher","DOI":"10.1038\/nrdp.2016.67"},{"key":"2026041100434384000_2025.02.10.637394v1.4","doi-asserted-by":"publisher","DOI":"10.2174\/1874364101004010052"},{"key":"2026041100434384000_2025.02.10.637394v1.5","doi-asserted-by":"publisher","DOI":"10.1097\/IJG.0b013e31815f52a8"},{"key":"2026041100434384000_2025.02.10.637394v1.6","doi-asserted-by":"publisher","DOI":"10.1002\/jcp.24524"},{"key":"2026041100434384000_2025.02.10.637394v1.7","doi-asserted-by":"publisher","DOI":"10.1111\/ceo.14027"},{"key":"2026041100434384000_2025.02.10.637394v1.8","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.13-13088"},{"key":"2026041100434384000_2025.02.10.637394v1.9","doi-asserted-by":"crossref","unstructured":"Soundararajan A , Ghag SA , Vuda SS , Wang T , Pattabiraman PP . 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