{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T13:02:06Z","timestamp":1789650126488,"version":"4.0.0"},"reference-count":187,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T00:00:00Z","timestamp":1789603200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Med. Sci.","Medical Sciences"],"abstract":"<jats:p>Keratoconus (KC) is a progressive corneal ectasia characterized by stromal thinning, steepening, and biomechanical instability. Although historically considered primarily a structural disorder, current evidence supports a multifactorial pathogenesis involving complex interactions among biomechanical, molecular, cellular, inflammatory, neurobiological, and environmental mechanisms. This narrative review provides an updated overview of KC pathophysiology, integrating current evidence across these interconnected domains. Focal reductions in corneal stiffness, altered viscoelasticity, collagen disorganization, and lamellar slippage contribute to progressive deformation under physiological stress. Oxidative stress and mitochondrial dysfunction promote reactive oxygen and nitrogen species accumulation, impaired antioxidant defenses, keratocyte apoptosis, and abnormal cellular metabolism. Dysregulated extracellular matrix turnover, characterized by increased matrix metalloproteinase activity, reduced inhibitor enzymes, altered cross-linking, and aberrant growth factor signaling, further compromises stromal integrity. Chronic low-grade para-inflammation, neurotrophic imbalance, and subbasal nerve plexus alterations may amplify proteolysis and defective tissue repair. Genetic and epigenetic susceptibility interacts with environmental and behavioral modifiers. Together, these processes form pathways that converge on focal stromal weakening and cone formation. Emerging technologies, including advanced biomechanical imaging, molecular biomarkers, multi-omics approaches, and artificial intelligence, may enable earlier detection and improve risk stratification. Further understanding the pathophysiology of KC may ultimately support the development of targeted therapies aimed at modifying the underlying disease mechanisms rather than addressing the structural consequences solely.<\/jats:p>","DOI":"10.3390\/medsci14050579","type":"journal-article","created":{"date-parts":[[2026,9,17]],"date-time":"2026-09-17T11:41:35Z","timestamp":1789645295000},"page":"579","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Update on the Physiopathology of Keratoconus"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6757-819X","authenticated-orcid":false,"given":"Raul Hernan","family":"Barcelo-Canton","sequence":"first","affiliation":[{"name":"Tecnologico de Monterrey, School of Medicine and Health Sciences, Institute of Ophthalmology and Visual Sciences, Monterrey 66278, Mexico"},{"name":"Instituto de Oftalmologia Fundacion Conde de Valenciana, Mexico City 06800, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1419-2109","authenticated-orcid":false,"given":"Alejandro","family":"Rodriguez-Garcia","sequence":"additional","affiliation":[{"name":"Tecnologico de Monterrey, School of Medicine and Health Sciences, Institute of Ophthalmology and Visual Sciences, Monterrey 66278, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3267-3915","authenticated-orcid":false,"given":"Enrique O.","family":"Graue-Hernandez","sequence":"additional","affiliation":[{"name":"Instituto de Oftalmologia Fundacion Conde de Valenciana, Mexico City 06800, Mexico"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6362-4898","authenticated-orcid":false,"given":"Jodhbir S.","family":"Mehta","sequence":"additional","affiliation":[{"name":"Ophthalmology & Visual Sciences Academic Clinical Programme (EYE-ACP), Duke-NUS Medical School, Singapore 169857, Singapore"},{"name":"Singapore Eye Research Institute, Singapore 169856, Singapore"},{"name":"Singapore National Eye Centre, 11 Third Hospital Ave., Singapore 168751, Singapore"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,9,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.preteyeres.2015.07.001","article-title":"Corneal Structure and Transparency","volume":"49","author":"Meek","year":"2015","journal-title":"Prog. 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