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Tear fluid hyperosmolality and reduced volume are key drivers of dry eye disease (DED) pathogenesis. We constructed a mathematical model to compute the composition and volume of tear fluid and epithelial cell compartments, with transport parameters specified for the mouse eye based on published data and in vivo measurements of ocular surface potential differences. The model accounted for transcellular and paracellular transport across the epithelia under open-circuit conditions utilizing flux equations for individual transport mechanisms, with mass balance constraints on solute and water content in cytoplasm and tear fluid. Model computations revealed a rough orthogonality between the determinants of tear fluid volume and osmolality in which lacrimal secretion and nasolacrimal drainage primarily regulate tear fluid volume, whereas evaporation and transepithelial osmosis primarily regulate tear fluid osmolality. Under DED conditions established by reduced lacrimal secretion and increased evaporation, the model predicted the efficacy of currently available DED therapies, including punctal plugs, humidification goggles, lacrimal gland stimulation, and artificial tear eye drops. The model also predicted the limited efficacy of anti-absorptive and pro-secretory drugs targeting epithelial ion transporters and the high efficacy of targeting epithelial water permeability or paracellular ion permeability. The modeling herein provided quantitative predictions to prioritize drug targets for DED to drive the development of novel therapies.<\/jats:p>","DOI":"10.1085\/jgp.202513958","type":"journal-article","created":{"date-parts":[[2026,5,22]],"date-time":"2026-05-22T13:19:58Z","timestamp":1779455998000},"update-policy":"https:\/\/doi.org\/10.1085\/jgp.crossmarkpolicy","source":"Crossref","is-referenced-by-count":1,"title":["Model of ocular surface ion and water transport predicts efficacy of dry eye therapeutics"],"prefix":"10.1085","volume":"158","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-4507-291X","authenticated-orcid":true,"given":"Varun","family":"Verma","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California, Berkeley 1 , Berkeley, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0003-2666-2432","authenticated-orcid":true,"given":"Ethan S.","family":"Lindgren","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California San Francisco 2 Department of Ophthalmology, , San Francisco, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-6004-5311","authenticated-orcid":true,"given":"Marc H.","family":"Levin","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California San Francisco 2 Department of Ophthalmology, , San Francisco, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5178-0199","authenticated-orcid":true,"given":"Onur","family":"Cil","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California San Francisco 3 Department of Pediatrics, , San Francisco, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0001-8414-5922","authenticated-orcid":true,"given":"Lukmanee","family":"Tradtrantip","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California San Francisco 4 Departments of Medicine and Physiology, , San Francisco, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1505-1321","authenticated-orcid":true,"given":"Rongshan","family":"Yan","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California San Francisco 2 Department of Ophthalmology, , San Francisco, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2327-5221","authenticated-orcid":true,"given":"Neel D.","family":"Pasricha","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California San Francisco 2 Department of Ophthalmology, , San Francisco, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3713-2202","authenticated-orcid":true,"given":"Alan S.","family":"Verkman","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/043mz5j54","id-type":"ROR","asserted-by":"publisher"}],"name":"University of California San Francisco 4 Departments of Medicine and Physiology, , San Francisco, CA,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2026,5,22]]},"reference":[{"key":"2026070210062613000_bib1","doi-asserted-by":"publisher","first-page":"613","DOI":"10.2147\/OPTH.S29431","article-title":"Validation and verification of the OPI 2.0 system","volume":"6","author":"Abelson","year":"2012","journal-title":"Clin. 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