{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:26:46Z","timestamp":1787030806424,"version":"build-2736575974"},"reference-count":46,"publisher":"MDPI AG","issue":"16","license":[{"start":{"date-parts":[[2026,8,16]],"date-time":"2026-08-16T00:00:00Z","timestamp":1786838400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01EY033758"],"award-info":[{"award-number":["R01EY033758"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["EY001792"],"award-info":[{"award-number":["EY001792"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"award":["R01EY033758"],"award-info":[{"award-number":["R01EY033758"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"award":["EY001792"],"award-info":[{"award-number":["EY001792"]}],"id":[{"id":"https:\/\/ror.org\/01cwqze88","id-type":"ROR","asserted-by":"publisher"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"crossref"}]},{"id":[{"id":"https:\/\/ror.org\/04drjs621","id-type":"ROR","asserted-by":"publisher"}]},{"name":"Research Scouts Program at the University of Michigan"},{"name":"Ono Pharmaceuticals Inc."}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>Corneal fibrosis is a major cause of visual impairment worldwide and is characterized by persistent stromal scarring that disrupts corneal transparency. Although transforming growth factor-\u03b2 (TGF-\u03b2)-mediated myofibroblast differentiation is well established, the mechanisms that sustain myofibroblast survival and persistence remain poorly understood. In this study, we investigated the role of the insulin-like growth factor (IGF) signaling axis in corneal myofibroblast survival and evaluated the therapeutic potential of linsitinib, a dual IGF-1 receptor (IGF-1R)\/insulin receptor (INSR) inhibitor. Primary corneal myofibroblasts were exposed to pro-apoptotic conditions and treated with IGF ligands in the presence or absence of linsitinib. The effects of IGF pathway inhibition were further examined in a mouse model of corneal fibrosis. IGF-1 and IGF-2 promoted myofibroblast survival under pro-apoptotic conditions, whereas pharmacologic inhibition of IGF-1R\/INSR signaling with linsitinib blocked these pro-survival effects. In vivo, linsitinib treatment reduced myofibroblast persistence and attenuated corneal fibrosis. These findings identify the IGF axis as a critical regulator of corneal myofibroblast survival and suggest that persistent fibrosis is maintained, in part, by IGF-dependent resistance to apoptosis. Targeting survival pathways rather than myofibroblast differentiation may represent a novel therapeutic strategy for the treatment of corneal fibrosis.<\/jats:p>","DOI":"10.3390\/ijms27167320","type":"journal-article","created":{"date-parts":[[2026,8,17]],"date-time":"2026-08-17T12:01:26Z","timestamp":1786968086000},"page":"7320","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Insulin-like Growth Factor Signaling Promotes Corneal Myofibroblast Survival and Sustains Corneal Fibrosis"],"prefix":"10.3390","volume":"27","author":[{"given":"Yunjeong","family":"Hwang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"},{"name":"Richard and Loan Hill Department of Biomedical Engineering, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung-No","family":"Son","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manoj","family":"Chaudhary","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eunbee","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minhyung","family":"Kim","sequence":"additional","affiliation":[{"name":"Departments of Urology and Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sungyong","family":"You","sequence":"additional","affiliation":[{"name":"Departments of Urology and Computational Biomedicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6279-9685","authenticated-orcid":false,"given":"Terry J.","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48105, USA"},{"name":"Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vinay Kumar","family":"Aakalu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Eye Institute, Medical College of Wisconsin, Milwaukee, WI 53226, USA"},{"name":"Department of Ophthalmology and Visual Sciences, Kellogg Eye Center, University of Michigan, Ann Arbor, MI 48105, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2561-8187","authenticated-orcid":false,"given":"Kyu-yeon","family":"Han","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology and Visual Sciences, Illinois Eye and Ear Infirmary, College of Medicine, University of Illinois Chicago, Chicago, IL 60612, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,8,16]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"e1221","DOI":"10.1016\/S2214-109X(17)30393-5","article-title":"Global causes of blindness and distance vision impairment 1990-2020: A systematic review and meta-analysis","volume":"5","author":"Flaxman","year":"2017","journal-title":"Lancet Glob. Health"},{"key":"ref_2","first-page":"214","article-title":"Corneal blindness: A global perspective","volume":"79","author":"Whitcher","year":"2001","journal-title":"Bull. World Health Organ."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1136\/bjophthalmol-2011-300539","article-title":"Global estimates of visual impairment: 2010","volume":"96","author":"Pascolini","year":"2012","journal-title":"Br. J. Ophthalmol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.1038\/nm.2807","article-title":"Mechanisms of fibrosis: Therapeutic translation for fibrotic disease","volume":"18","author":"Wynn","year":"2012","journal-title":"Nat. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1172\/JCI93563","article-title":"Resolution of organ fibrosis","volume":"128","author":"Jun","year":"2018","journal-title":"J. Clin. Investig."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1038\/sj.jid.5700811","article-title":"The inflammation-fibrosis link? A Jekyll and Hyde role for blood cells during wound repair","volume":"127","author":"Stramer","year":"2007","journal-title":"J. Investig. Dermatol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1138","DOI":"10.1056\/NEJMra1300575","article-title":"Fibrosis\u2014A common pathway to organ injury and failure","volume":"372","author":"Rockey","year":"2015","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"719","DOI":"10.1084\/jem.135.4.719","article-title":"Granulation tissue as a contractile organ. A study of structure and function","volume":"135","author":"Gabbiani","year":"1972","journal-title":"J. Exp. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"314","DOI":"10.1038\/nature07039","article-title":"Wound repair and regeneration","volume":"453","author":"Gurtner","year":"2008","journal-title":"Nature"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"a008748","DOI":"10.1101\/cshperspect.a008748","article-title":"Clearing the dead: Apoptotic cell sensing, recognition, engulfment, and digestion","volume":"5","author":"Ravichandran","year":"2013","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S84","DOI":"10.1111\/j.1440-1746.2006.04584.x","article-title":"Hepatic stellate cells and the reversal of fibrosis","volume":"21","author":"Kisseleva","year":"2006","journal-title":"J. Gastroenterol. Hepatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"450","DOI":"10.1016\/j.immuni.2016.02.015","article-title":"Macrophages in Tissue Repair, Regeneration, and Fibrosis","volume":"44","author":"Wynn","year":"2016","journal-title":"Immunity"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"752","DOI":"10.12688\/f1000research.8190.1","article-title":"The myofibroblast in wound healing and fibrosis: Answered and unanswered questions","volume":"5","author":"Gabbiani","year":"2016","journal-title":"F1000Research"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1083\/jcb.142.3.873","article-title":"The fibronectin domain ED-A is crucial for myofibroblastic phenotype induction by transforming growth factor-beta1","volume":"142","author":"Serini","year":"1998","journal-title":"J. Cell Biol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1145","DOI":"10.1007\/s00018-015-2110-0","article-title":"The myofibroblast, a key cell in normal and pathological tissue repair","volume":"73","author":"Darby","year":"2016","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1046\/j.1442-9071.2001.00368.x","article-title":"Transforming growth factor-beta1 induces alpha-smooth muscle actin expression and fibronectin synthesis in cultured human retinal pigment epithelial cells","volume":"29","author":"Stocks","year":"2001","journal-title":"Clin. Exp. Ophthalmol."},{"key":"ref_17","first-page":"696","article-title":"Induction of alpha-smooth muscle actin by transforming growth factor-beta1 in quiescent human breast gland fibroblasts. Implications for myofibroblast generation in breast neoplasia","volume":"68","author":"Petersen","year":"1993","journal-title":"Lab. Investig."},{"key":"ref_18","first-page":"56","article-title":"Apoptosis mediates the decrease in cellularity during the transition between granulation tissue and scar","volume":"146","author":"Desmouliere","year":"1995","journal-title":"Am. J. Pathol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"538","DOI":"10.1172\/JCI1018","article-title":"Mechanisms of spontaneous resolution of rat liver fibrosis. Hepatic stellate cell apoptosis and reduced hepatic expression of metalloproteinase inhibitors","volume":"102","author":"Iredale","year":"1998","journal-title":"J. Clin. Investig."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"658","DOI":"10.1165\/ajrcmb.21.6.3720","article-title":"Inhibition of myofibroblast apoptosis by transforming growth factor beta(1)","volume":"21","author":"Zhang","year":"1999","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"863","DOI":"10.1016\/S0092-8674(00)81270-2","article-title":"PDGF-A signaling is a critical event in lung alveolar myofibroblast development and alveogenesis","volume":"85","author":"Bostrom","year":"1996","journal-title":"Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1007\/s10875-005-8217-6","article-title":"The anti-death machinery in IKK\/NF-kappaB signaling","volume":"25","author":"Luo","year":"2005","journal-title":"J. Clin. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2153","DOI":"10.1097\/00007632-200009010-00002","article-title":"Anti-apoptotic effects of IGF-1 and PDGF on human intervertebral disc cells In Vitro","volume":"25","author":"Gruber","year":"2000","journal-title":"Spine"},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"Tsai, T.C., Shih, C.C., Chien, H.P., Yang, A.H., Lu, J.K., and Lu, J.H. (2018). Anti-apoptotic effects of IGF-I on mortality and dysmorphogenesis in tbx5-deficient zebrafish embryos. BMC Dev. Biol., 18.","DOI":"10.1186\/s12861-017-0161-1"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1023\/A:1006208721167","article-title":"Insulin-like growth factor (IGF)-I rescues breast cancer cells from chemotherapy-induced cell death\u2014Proliferative and anti-apoptotic effects","volume":"56","author":"Gooch","year":"1999","journal-title":"Breast Cancer Res. Treat."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1016\/j.jshs.2020.11.009","article-title":"IGF1-PI3K-induced physiological cardiac hypertrophy: Implications for new heart failure therapies, biomarkers, and predicting cardiotoxicity","volume":"10","author":"Tai","year":"2021","journal-title":"J. Sport Health Sci."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1002\/glia.20653","article-title":"IGF-1 receptor-mediated ERK\/MAPK signaling couples status epilepticus to progenitor cell proliferation in the subgranular layer of the dentate gyrus","volume":"56","author":"Choi","year":"2008","journal-title":"Glia"},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Epaud, R., Aubey, F., Xu, J., Chaker, Z., Clemessy, M., Dautin, A., Ahamed, K., Bonora, M., Hoyeau, N., and Flejou, J.F. (2012). Knockout of insulin-like growth factor-1 receptor impairs distal lung morphogenesis. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0048071"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.matbio.2017.06.003","article-title":"Injury and defective regeneration of the epithelial basement membrane in corneal fibrosis: A paradigm for fibrosis in other organs?","volume":"64","author":"Wilson","year":"2017","journal-title":"Matrix Biol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"110","DOI":"10.1016\/j.exer.2014.09.012","article-title":"The corneal fibrosis response to epithelial-stromal injury","volume":"142","author":"Torricelli","year":"2016","journal-title":"Exp. Eye Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1165\/rcmb.2015-0388OC","article-title":"Smooth Muscle Insulin-Like Growth Factor-1 Mediates Hypoxia-Induced Pulmonary Hypertension in Neonatal Mice","volume":"55","author":"Sun","year":"2016","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1111\/bph.13693","article-title":"Inhibiting thyrotropin\/insulin-like growth factor 1 receptor crosstalk to treat Graves\u2019 ophthalmopathy: Studies in orbital fibroblasts In Vitro","volume":"174","author":"Place","year":"2017","journal-title":"Br. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"115084","DOI":"10.1016\/j.intimp.2025.115084","article-title":"Targeting insulin-like growth factor 1 signaling with Linsitinib to modulate fibroblast plasticity and attenuate pulmonary fibrosis","volume":"161","author":"Zhu","year":"2025","journal-title":"Int. Immunopharmacol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1038\/s41598-024-83193-x","article-title":"Effects of linsitinib on M22 and IGF:1-treated 3D spheroids of human orbital fibroblasts","volume":"15","author":"Hikage","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"7647","DOI":"10.1167\/iovs.10-5625","article-title":"Insulin growth factor promotes human corneal fibroblast network formation In Vitro","volume":"52","author":"Berthaut","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_36","first-page":"1742","article-title":"Effect of growth factors on collagen lattice contraction by human keratocytes","volume":"33","author":"Assouline","year":"1992","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1167\/iovs.05-0826","article-title":"Insulin-like growth factor-1 induces migration and expression of laminin-5 in cultured human corneal epithelial cells","volume":"47","author":"Lee","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1153","DOI":"10.4155\/fmc.09.89","article-title":"Discovery of OSI-906: A selective and orally efficacious dual inhibitor of the IGF-1 receptor and insulin receptor","volume":"1","author":"Mulvihill","year":"2009","journal-title":"Future Med. Chem."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1019","DOI":"10.1189\/jlb.0504288","article-title":"IL-4-induced macrophage-derived IGF-I protects myofibroblasts from apoptosis following growth factor withdrawal","volume":"76","author":"Wynes","year":"2004","journal-title":"J. Leukoc. Biol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"101424","DOI":"10.1016\/j.resinv.2026.101424","article-title":"Insulin-like growth factor 1 by lung fibroblasts from patients with idiopathic pulmonary fibrosis contributes to the development of fibrosis","volume":"64","author":"Kitabatake","year":"2026","journal-title":"Respir. Investig."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Waldrep, K.M., Rodgers, J.I., Garrett, S.M., Wolf, B.J., and Feghali-Bostwick, C.A. (2023). The Role of SOX9 in IGF-II-Mediated Pulmonary Fibrosis. Int. J. Mol. Sci., 24.","DOI":"10.3390\/ijms241411234"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"877","DOI":"10.1007\/s11626-022-00730-6","article-title":"IGF-1 increases survival of CD4+ lineage in a 2D model of thymocyte\/thymic stromal cell co-culture","volume":"58","author":"Lins","year":"2022","journal-title":"Vitr. Cell. Dev. Biol. Anim."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"736104","DOI":"10.1155\/2015\/736104","article-title":"Role and Importance of IGF-1 in Traumatic Brain Injuries","volume":"2015","author":"Mangiola","year":"2015","journal-title":"Biomed. Res. Int."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1186\/1479-5876-10-224","article-title":"Human conditions of insulin-like growth factor-I (IGF-I) deficiency","volume":"10","author":"Puche","year":"2012","journal-title":"J. Transl. Med."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Stuard, W.L., Titone, R., and Robertson, D.M. (2020). The IGF\/Insulin-IGFBP Axis in Corneal Development, Wound Healing, and Disease. Front. Endocrinol., 11.","DOI":"10.3389\/fendo.2020.00024"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1038\/s41587-019-0048-8","article-title":"Tubuloids derived from human adult kidney and urine for personalized disease modeling","volume":"37","author":"Schutgens","year":"2019","journal-title":"Nat. Biotechnol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7320\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:28:51Z","timestamp":1787027331000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/16\/7320"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,16]]},"references-count":46,"journal-issue":{"issue":"16","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27167320"],"URL":"https:\/\/doi.org\/10.3390\/ijms27167320","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,16]]}}}