{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T09:43:56Z","timestamp":1785923036690,"version":"3.56.0"},"reference-count":84,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T00:00:00Z","timestamp":1785888000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Keratoconus (KC) is a degenerative corneal disease, characterized by stromal thinning and abnormal ECM remodeling, leading to fibrosis. Corneal fibrosis is a leading cause of visual impairment. Corneal stromal keratocytes differentiate into myofibroblasts, which alters extracellular matrix (ECM) protein deposition. Nintedanib (NIN) is an antifibrotic FDA-approved tyrosine kinase inhibitor, but its function in the cornea is largely unknown. This study examined the impact of NIN within the human corneal stromal microenvironment. Healthy corneal stromal fibroblasts (HCFs) and KC fibroblasts (HKCs) in 2D and 3D in vitro cultures were treated with 1 \u03bcM or 2.5 \u03bcM NIN. Cell types were evaluated in 2D cultures for metabolic activity, viability, and migration. Protein expression of alpha-smooth muscle actin (\u03b1-SMA), collagens (COLs) 1, 3, and 5, cellular fibronectin containing extra domain A (EDA-FN), and thrombospondin-1 (TSP-1) were evaluated in 3D cultures. NIN reduced metabolic activity in HKCs without affecting cell viability. NIN reduced cell migration, downregulated COL3, COL5, EDA-FN, and TSP-1 expression in HCFs and HKCs. COL1 was upregulated in HCFs, whereas \u03b1-SMA was upregulated in HKCs. Overall, these findings demonstrate that NIN modulates corneal stromal cell migration and fibrotic marker expression, highlighting its potential as a therapeutic strategy for reducing corneal fibrosis associated with keratoconus.<\/jats:p>","DOI":"10.3390\/biom16081137","type":"journal-article","created":{"date-parts":[[2026,8,5]],"date-time":"2026-08-05T08:14:46Z","timestamp":1785917686000},"page":"1137","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["In Vitro Assessment of Nintedanib in Keratoconus Corneal Stromal Microenvironment"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-8146-089X","authenticated-orcid":false,"given":"Yasamin","family":"Moradi","sequence":"first","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"},{"name":"College of Biomedical and Translational Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"},{"name":"Department of Family Medicine, Texas College of Osteopathic Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9081-3829","authenticated-orcid":false,"given":"Pawan","family":"Shrestha","sequence":"additional","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"},{"name":"College of Biomedical and Translational Sciences, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"},{"name":"Department of Family Medicine, Texas College of Osteopathic Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0719-8059","authenticated-orcid":false,"given":"Steve","family":"Mabry","sequence":"additional","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"},{"name":"Department of Family Medicine, Texas College of Osteopathic Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Purnima","family":"Sharma","sequence":"additional","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"},{"name":"Department of Family Medicine, Texas College of Osteopathic Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karanpreet S.","family":"Multani","sequence":"additional","affiliation":[{"name":"Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, Oklahoma City, OK 73104, USA"},{"name":"College of Medicine, University of Oklahoma Health Sciences Center, 800 Stanton L. Young, Oklahoma City, OK 73117, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1090-5025","authenticated-orcid":false,"given":"Kamran M.","family":"Riaz","sequence":"additional","affiliation":[{"name":"Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L. Young Blvd, Oklahoma City, OK 73104, USA"},{"name":"College of Medicine, University of Oklahoma Health Sciences Center, 800 Stanton L. Young, Oklahoma City, OK 73117, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8761-3824","authenticated-orcid":false,"given":"Dimitrios","family":"Karamichos","sequence":"additional","affiliation":[{"name":"North Texas Eye Research Institute, University of North Texas Health, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"},{"name":"Department of Family Medicine, Texas College of Osteopathic Medicine, University of North Texas Health Science Center, 3500 Camp Bowie Blvd, Fort Worth, TX 76107, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"297","DOI":"10.1016\/S0039-6257(97)00119-7","article-title":"Keratoconus","volume":"42","author":"Rabinowitz","year":"1998","journal-title":"Surv. Ophthalmol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"101559","DOI":"10.1016\/j.clae.2021.101559","article-title":"Keratoconus: An updated review","volume":"45","author":"Carracedo","year":"2022","journal-title":"Contact Lens Anterior Eye"},{"key":"ref_3","unstructured":"Asimellis, G., and Kaufman, E.J. (2024). Keratoconus. StatPearls, StatPearls Publishing."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1136\/bjophthalmol-2013-304132","article-title":"Evaluation of corneal elevation, pachymetry and keratometry in keratoconic eyes with respect to the stage of Amsler-Krumeich classification","volume":"98","author":"Kamiya","year":"2014","journal-title":"Br. J. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.preteyeres.2015.07.002","article-title":"Progress in corneal wound healing","volume":"49","author":"Ljubimov","year":"2015","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_6","first-page":"997","article-title":"Extracellular matrix alterations in human corneas with bullous keratopathy","volume":"37","author":"Ljubimov","year":"1996","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"107709","DOI":"10.1016\/j.exer.2019.107709","article-title":"Corneal injury: Clinical and molecular aspects","volume":"186","author":"Barrientez","year":"2019","journal-title":"Exp. Eye Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1680","DOI":"10.1002\/ar.24090","article-title":"Keratoconus at a molecular level: A review","volume":"303","author":"Volatier","year":"2020","journal-title":"Anat. Rec."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1382","DOI":"10.1167\/iovs.09-3860","article-title":"Human corneal fibrosis: An in vitro model","volume":"51","author":"Karamichos","year":"2010","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"28","DOI":"10.1167\/iovs.61.2.28","article-title":"Fibrocytes, wound healing, and corneal fibrosis","volume":"61","author":"Wilson","year":"2020","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Pardali, E., Sanchez-Duffhues, G., Gomez-Puerto, M.C., and Ten Dijke, P. (2017). TGF-\u03b2-induced endothelial-mesenchymal transition in fibrotic diseases. Int. J. Mol. Sci., 18.","DOI":"10.3390\/ijms18102157"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"115317","DOI":"10.1016\/j.addr.2024.115317","article-title":"Corneal fibrosis: From in vitro models to current and upcoming drug and gene medicines","volume":"209","author":"Cubillo","year":"2024","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"853","DOI":"10.1111\/j.1523-1755.1998.00820.x","article-title":"Expression of connective tissue growth factor in human renal fibrosis","volume":"53","author":"Ito","year":"1998","journal-title":"Kidney Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"101530","DOI":"10.1016\/j.jbc.2021.101530","article-title":"The interplay of fibroblasts, the extracellular matrix, and inflammation in scar formation","volume":"298","author":"Moretti","year":"2022","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ortiz-Zapater, E., Signes-Costa, J., Montero, P., and Roger, I. (2022). Lung fibrosis and fibrosis in the lungs: Is it all about myofibroblasts?. Biomedicines, 10.","DOI":"10.3390\/biomedicines10061423"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1002\/path.2277","article-title":"Cellular and molecular mechanisms of fibrosis","volume":"214","author":"Wynn","year":"2008","journal-title":"J. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1016\/S0002-9440(10)63254-3","article-title":"Advanced glycation end-products induce connective tissue growth factor-mediated renal fibrosis predominantly through transforming growth factor \u03b2-independent pathway","volume":"165","author":"Zhou","year":"2004","journal-title":"Am. J. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"298","DOI":"10.1002\/path.4104","article-title":"The myofibroblast matrix: Implications for tissue repair and fibrosis","volume":"229","author":"Klingberg","year":"2013","journal-title":"J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mia, M.M., Boersema, M., and Bank, R.A. (2014). Interleukin-1\u03b2 attenuates myofibroblast formation and extracellular matrix production in dermal and lung fibroblasts exposed to transforming growth factor-\u03b21. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0091559"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2780","DOI":"10.1111\/jcmm.12661","article-title":"The I\u03baB kinase inhibitor ACHP strongly attenuates TGF \u03b21-induced myofibroblast formation and collagen synthesis","volume":"19","author":"Mia","year":"2015","journal-title":"J. Cell Mol. Med."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1774","DOI":"10.1096\/fasebj.13.13.1774","article-title":"Connective tissue growth factor mediates transforming growth factor \u03b2-induced collagen synthesis: Down-regulation by cAMP","volume":"13","author":"Duncan","year":"1999","journal-title":"FASEB J."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5068","DOI":"10.1167\/iovs.11-7191","article-title":"Regulation of Fibronectin-EDA through CTGF Domain\u2013Specific Interactions with TGF\u03b22 and Its Receptor TGF\u03b2RII","volume":"52","author":"Khankan","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1080\/14656566.2023.2213436","article-title":"An update on current and emerging drug treatments for idiopathic pulmonary fibrosis","volume":"24","author":"Trachalaki","year":"2023","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1147","DOI":"10.2147\/DDDT.S130297","article-title":"Inhibition of lymphangiogenesis in vitro and in vivo by the multikinase inhibitor nintedanib","volume":"11","author":"Lin","year":"2017","journal-title":"Drug Des. Devel Ther."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1053","DOI":"10.1021\/jm501562a","article-title":"Nintedanib: From discovery to the clinic","volume":"58","author":"Roth","year":"2015","journal-title":"J. Med. Chem."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Regan, E., Sibley, R.C., Cenik, B.K., Silva, A., Girard, L., Minna, J.D., and Dellinger, M.T. (2016). Identification of gene expression differences between lymphangiogenic and non-lymphangiogenic non-small cell lung cancer cell lines. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0150963"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"494","DOI":"10.1124\/jpet.117.244129","article-title":"Triple angiokinase inhibitor nintedanib directly inhibits tumor cell growth and induces tumor shrinkage via blocking oncogenic receptor tyrosine kinases","volume":"364","author":"Hilberg","year":"2018","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"883","DOI":"10.1136\/annrheumdis-2014-207109","article-title":"Nintedanib inhibits fibroblast activation and ameliorates fibrosis in preclinical models of systemic sclerosis","volume":"75","author":"Huang","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1186\/s12931-022-02116-4","article-title":"Nintedanib modulates type III collagen turnover in viable precision-cut lung slices from bleomycin-treated rats and patients with pulmonary fibrosis","volume":"23","author":"Hesse","year":"2022","journal-title":"Respir. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1165\/rcmb.2016-0217OC","article-title":"A novel antifibrotic mechanism of nintedanib and pirfenidone. Inhibition of collagen fibril assembly","volume":"57","author":"Ishikawa","year":"2017","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1900161","DOI":"10.1183\/13993003.00161-2019","article-title":"Potential of nintedanib in treatment of progressive fibrosing interstitial lung diseases","volume":"54","author":"Wollin","year":"2019","journal-title":"Eur. Respir. J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"E2496","DOI":"10.1002\/lary.29618","article-title":"Antifibrotic role of nintedanib in tracheal stenosis after a tracheal wound","volume":"131","author":"Fan","year":"2021","journal-title":"Laryngoscope"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e01028","DOI":"10.1002\/prp2.1028","article-title":"Prevention of bleomycin-induced lung fibrosis via inhibition of the MRTF\/SRF transcription pathway","volume":"10","author":"Pawelec","year":"2022","journal-title":"Pharmacol. Res. Perspect."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1124\/jpet.113.208223","article-title":"Antifibrotic and anti-inflammatory activity of the tyrosine kinase inhibitor nintedanib in experimental models of lung fibrosis","volume":"349","author":"Wollin","year":"2014","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1007\/s40265-021-01487-0","article-title":"Nintedanib: A review in fibrotic interstitial lung diseases","volume":"81","author":"Lamb","year":"2021","journal-title":"Drugs"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1578","DOI":"10.1080\/02713683.2022.2129071","article-title":"Effect of Nintedanib Nanothermoreversible Hydrogel on Neovascularization in an Ocular Alkali Burn Rat Model","volume":"47","author":"Liu","year":"2022","journal-title":"Curr. Eye Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"879","DOI":"10.18240\/ijo.2020.06.04","article-title":"Effect of nintedanib thermo-sensitive hydrogel on neovascularization in alkali burn rat model","volume":"13","author":"Gong","year":"2020","journal-title":"Int. J. Ophthalmol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1666","DOI":"10.18240\/ijo.2021.11.04","article-title":"Inhibition of corneal neovascularization by topical application of nintedanib in rabbit models","volume":"14","author":"Chen","year":"2021","journal-title":"Int. J. Ophthalmol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1039\/D3BM01349A","article-title":"An active transport dual adaptive nanocarrier designed to overcome the corneal microenvironment for neovascularization therapy","volume":"12","author":"Wang","year":"2024","journal-title":"Biomater. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Akhter, M.H., Ahmad, I., Alshahrani, M.Y., Al-Harbi, A.I., Khalilullah, H., Afzal, O., Altamimi, A.S., Najib Ullah, S.N.M., Ojha, A., and Karim, S. (2022). Drug delivery challenges and current progress in nanocarrier-based ocular therapeutic system. Gels, 8.","DOI":"10.3390\/gels8020082"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2508726","DOI":"10.1002\/adma.202508726","article-title":"Advanced nanotechnology-driven innovations for corneal neovascularization therapy: Smart drug delivery and enhanced treatment strategies","volume":"37","author":"Huang","year":"2025","journal-title":"Adv. Mater."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"914","DOI":"10.18240\/ijo.2022.06.08","article-title":"Evaluation of nintedanib as a new postoperative antiscarring agent in experimental extraocular muscle surgery","volume":"15","author":"Bicaklioglu","year":"2022","journal-title":"Int. J. Ophthalmol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"110764","DOI":"10.1016\/j.exer.2025.110764","article-title":"Contact lens delivery improves therapeutic efficacy of nintedanib in rabbit eyes with alkali burn","volume":"263","author":"Sharma","year":"2026","journal-title":"Exp. Eye Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"109431","DOI":"10.1016\/j.exer.2023.109431","article-title":"The anti-scar effect of tyrosine-kinase inhibitor nintedanib in experimental glaucoma filtration surgery in rabbits","volume":"229","author":"Yuksel","year":"2023","journal-title":"Exp. Eye Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1038\/s41433-019-0736-0","article-title":"Biology of corneal fibrosis: Soluble mediators, integrins, and extracellular vesicles","volume":"34","author":"McKay","year":"2020","journal-title":"Eye"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"e20190103","DOI":"10.1084\/jem.20190103","article-title":"Transforming growth factor\u2013\u03b2 in tissue fibrosis","volume":"217","author":"Frangogiannis","year":"2020","journal-title":"J. Exp. Med."},{"key":"ref_47","doi-asserted-by":"crossref","unstructured":"Escandon, P., Nicholas, S.E., Cunningham, R.L., Murphy, D.A., Riaz, K.M., and Karamichos, D. (2022). The role of estriol and estrone in keratoconic stromal sex hormone receptors. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020916"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"760","DOI":"10.3390\/jfb3040760","article-title":"Novel in vitro model for keratoconus disease","volume":"3","author":"Karamichos","year":"2012","journal-title":"J. Funct. Biomater."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"6612","DOI":"10.1167\/iovs.13-12861","article-title":"TGF-\u03b23 stimulates stromal matrix assembly by human corneal keratocyte-like cells","volume":"54","author":"Karamichos","year":"2013","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"17534666241232561","DOI":"10.1177\/17534666241232561","article-title":"Impact of antifibrotic therapy on disease progression, all-cause mortality, and risk of acute exacerbation in non-IPF fibrosing interstitial lung diseases: Evidence from a meta-analysis of randomized controlled trials and prospective controlled studies","volume":"18","author":"Li","year":"2024","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1038\/bjc.2017.270","article-title":"Nintedanib selectively inhibits the activation and tumour-promoting effects of fibroblasts from lung adenocarcinoma patients","volume":"117","author":"Gabasa","year":"2017","journal-title":"Br. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"9445735","DOI":"10.1155\/sci\/9445735","article-title":"Human Umbilical Cord\u2013Mesenchymal Stem Cells Combined with Low Dosage Nintedanib Rather than Using Alone Mitigates Pulmonary Fibrosis in Mice","volume":"2025","author":"Qiu","year":"2025","journal-title":"Stem Cells Int."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Widjaja, A.A., Viswanathan, S., Jinrui, D., Singh, B.K., Tan, J., Wei Ting, J.G., Lamb, D., Shekeran, S.G., George, B.L., and Schafer, S. (2021). Molecular dissection of pro-fibrotic IL11 signaling in cardiac and pulmonary fibroblasts. Front. Mol. Biosci., 8.","DOI":"10.3389\/fmolb.2021.740650"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1111\/aos.16736","article-title":"Early findings in a randomised controlled trial on crosslinking protocols using isoosmolar and hypoosmolar riboflavin for the treatment of progressive keratoconus","volume":"103","author":"Gustafsson","year":"2025","journal-title":"Acta Ophthalmol."},{"key":"ref_55","first-page":"727","article-title":"Keratoconus treatment with corneal collagen crosslinking","volume":"69","author":"Ismaili","year":"2025","journal-title":"Knowl.-Int. J."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1002\/cbf.3122","article-title":"Quercetin modulates keratoconus metabolism in vitro","volume":"33","author":"McKay","year":"2015","journal-title":"Cell Biochem. Funct."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"111371","DOI":"10.1016\/j.biopha.2021.111371","article-title":"The therapeutic use of quercetin in ophthalmology: Recent applications","volume":"137","author":"Zhao","year":"2021","journal-title":"Biomed. Pharmacother."},{"key":"ref_58","doi-asserted-by":"crossref","unstructured":"McKay, T.B., Emmitte, K.A., German, C., and Karamichos, D. (2023). Quercetin and related analogs as therapeutics to promote tissue repair. Bioengineering, 10.","DOI":"10.3390\/bioengineering10101127"},{"key":"ref_59","doi-asserted-by":"crossref","unstructured":"Ogata, F.T., Verma, S., Coulson-Thomas, V.J., and Gesteira, T.F. (2024). TGF-\u03b2-based therapies for treating ocular surface disorders. Cells, 13.","DOI":"10.3390\/cells13131105"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1097\/00003226-199703000-00010","article-title":"Inhibition of corneal fibrosis by topical application of blocking antibodies to TGF\u03b2 in the rabbit","volume":"16","author":"Jester","year":"1997","journal-title":"Cornea"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"12517","DOI":"10.1038\/s41598-017-12598-8","article-title":"Human in vitro model reveals the effects of collagen cross-linking on keratoconus pathogenesis","volume":"7","author":"Sharif","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.joco.2017.11.002","article-title":"Updates on managements for keratoconus","volume":"30","author":"Mohammadpour","year":"2018","journal-title":"J. Curr. Ophthalmol."},{"key":"ref_63","first-page":"577","article-title":"Keratoconus in vitro and the key players of the TGF-\u03b2 pathway","volume":"21","author":"Priyadarsini","year":"2015","journal-title":"Mol. Vis."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1177\/10807683251361725","article-title":"Nonsurgical Therapies for Preventing Corneal Scarring: A Systematic Review of the Past Decade","volume":"41","author":"Xia","year":"2025","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1517\/14656566.2012.673588","article-title":"Pharmacotherapy of corneal transplantation","volume":"13","author":"Ziaei","year":"2012","journal-title":"Expert Opin. Pharmacother."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Tsai, C.-H., Liu, E., Phan, A., Lu, K.L., and Mei, H. (2023). NBL1 Reduces Corneal Fibrosis and Scar Formation after Wounding. Biomolecules, 13.","DOI":"10.3390\/biom13111570"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.exer.2014.09.012","article-title":"The corneal fibrosis response to epithelial\u2013stromal injury","volume":"142","author":"Torricelli","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.rmed.2016.02.001","article-title":"Nintedanib in patients with idiopathic pulmonary fibrosis: Combined evidence from the TOMORROW and INPULSIS\u00ae trials","volume":"113","author":"Richeldi","year":"2016","journal-title":"Respir. Med."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1753466618800618","DOI":"10.1177\/1753466618800618","article-title":"Nintedanib in the management of idiopathic pulmonary fibrosis: Clinical trial evidence and real-world experience","volume":"12","author":"Hayton","year":"2018","journal-title":"Ther. Adv. Respir. Dis."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"2000085","DOI":"10.1183\/13993003.00085-2020","article-title":"The natural history of progressive fibrosing interstitial lung diseases","volume":"55","author":"Brown","year":"2020","journal-title":"Eur. Respir. J."},{"key":"ref_71","first-page":"789","article-title":"Nintedanib inhibits TGF-beta-induced myofibroblast transdifferentiation in human Tenon\u2019s fibroblasts","volume":"24","author":"Lin","year":"2018","journal-title":"Mol. Vis."},{"key":"ref_72","doi-asserted-by":"crossref","unstructured":"Ghasemi, M., Turnbull, T., Sebastian, S., and Kempson, I. (2021). The MTT Assay: Utility, Limitations, Pitfalls, and Interpretation in Bulk and Single-Cell Analysis. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms222312827"},{"key":"ref_73","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1038\/s41420-022-01207-x","article-title":"Drug toxicity assessment: Cell proliferation versus cell death","volume":"8","author":"Sazonova","year":"2022","journal-title":"Cell Death Discov."},{"key":"ref_74","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1038\/s41401-020-0381-y","article-title":"Nintedanib inhibits keloid fibroblast functions by blocking the phosphorylation of multiple kinases and enhancing receptor internalization","volume":"41","author":"Zhou","year":"2020","journal-title":"Acta Pharmacol. Sin."},{"key":"ref_75","doi-asserted-by":"crossref","first-page":"6103","DOI":"10.1111\/jcmm.16518","article-title":"Nintedanib attenuates peritoneal fibrosis by inhibiting mesothelial-to-mesenchymal transition, inflammation and angiogenesis","volume":"25","author":"Liu","year":"2021","journal-title":"J. Cell Mol. Med."},{"key":"ref_76","doi-asserted-by":"crossref","first-page":"1434","DOI":"10.1183\/09031936.00174914","article-title":"Mode of action of nintedanib in the treatment of idiopathic pulmonary fibrosis","volume":"45","author":"Wollin","year":"2015","journal-title":"Eur. Respir. J."},{"key":"ref_77","doi-asserted-by":"crossref","first-page":"984","DOI":"10.1136\/thx.50.9.984","article-title":"Enhanced migration of fibroblasts derived from lungs with fibrotic lesions","volume":"50","author":"Suganuma","year":"1995","journal-title":"Thorax"},{"key":"ref_78","doi-asserted-by":"crossref","first-page":"e13281","DOI":"10.14814\/phy2.13281","article-title":"Matrix stiffness regulates migration of human lung fibroblasts","volume":"5","author":"Asano","year":"2017","journal-title":"Physiol. Rep."},{"key":"ref_79","doi-asserted-by":"crossref","first-page":"172","DOI":"10.1186\/s12931-017-0654-2","article-title":"Anti-fibrotic efficacy of nintedanib in pulmonary fibrosis via the inhibition of fibrocyte activity","volume":"18","author":"Sato","year":"2017","journal-title":"Respir. Res."},{"key":"ref_80","doi-asserted-by":"crossref","first-page":"1131","DOI":"10.1007\/s40262-019-00766-0","article-title":"Clinical pharmacokinetics and pharmacodynamics of nintedanib","volume":"58","author":"Wind","year":"2019","journal-title":"Clin. Pharmacokinet."},{"key":"ref_81","doi-asserted-by":"crossref","first-page":"G807","DOI":"10.1152\/ajpgi.00447.2014","article-title":"Novel insights into the function and dynamics of extracellular matrix in liver fibrosis","volume":"308","author":"Karsdal","year":"2015","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_82","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1165\/rcmb.2014-0445OC","article-title":"Novel Mechanisms for the Antifibrotic Action of Nintedanib","volume":"54","author":"Rangarajan","year":"2016","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_83","doi-asserted-by":"crossref","first-page":"205","DOI":"10.1186\/s13075-021-02555-2","article-title":"Nintedanib downregulates the transition of cultured systemic sclerosis fibrocytes into myofibroblasts and their pro-fibrotic activity","volume":"23","author":"Cutolo","year":"2021","journal-title":"Arthritis Res. Ther."},{"key":"ref_84","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1186\/s12931-014-0157-3","article-title":"Anti-fibrotic effects of nintedanib in lung fibroblasts derived from patients with idiopathic pulmonary fibrosis","volume":"15","author":"Hostettler","year":"2014","journal-title":"Respir. 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