{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:30:43Z","timestamp":1786595443432,"version":"build-2736575974"},"reference-count":44,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T00:00:00Z","timestamp":1786579200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100006245","name":"Ministry of Science and Technology, Israel","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100006245","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Endocrinol."],"abstract":"<jats:p>\n                    Graves\u2019 orbitopathy (GO) is characterized by inflammation, hyaluronan accumulation, tissue expansion, and fibrosis of orbital tissues, while effective antifibrotic medical therapies remain limited. Dipeptidyl peptidase-4 inhibitors (DPP4i), widely used for type 2 diabetes, have been reported to modulate fibroblast activity and fibrotic responses in several organs. This study investigated the effects of DPP4i on primary human orbital fibroblasts and explored their potential relevance to GO. Orbital fibroblasts were obtained from patients with GO and non-GO controls. DPP4 protein expression was assessed by Western blotting. The effects of linagliptin and sitagliptin on fibroblast proliferation, myofibroblastic differentiation, adipogenesis, and hyaluronan production were evaluated using DAPI nuclei counts, \u03b1-smooth muscle actin (\u03b1-SMA) immunofluorescence and Western blotting, Oil Red O staining, and ELISA, respectively. DPP4 protein was detected in orbital fibroblasts from both GO and non-GO groups. Linagliptin and sitagliptin significantly reduced transforming growth factor-\u03b2 (TGF-\u03b2)-induced \u03b1-SMA expression in GO fibroblasts, whereas their effects in non-GO fibroblasts were modest. Both linagliptin and sitagliptin significantly suppressed interleukin-1\u03b2 (IL-1\u03b2)-stimulated hyaluronan production in GO and non-GO fibroblasts. Neither inhibitor significantly altered DAPI-based cell number measurements or lipid accumulation in either group. These findings provide\n                    <jats:italic>in vitro<\/jats:italic>\n                    evidence that DPP4i modulate selected orbital fibroblast phenotypes related to myofibroblastic differentiation and cytokine-induced hyaluronan production. Further mechanistic, pharmacokinetic,\n                    <jats:italic>in vivo<\/jats:italic>\n                    , and clinical studies are warranted to clarify their relevance to GO-related tissue remodeling.\n                  <\/jats:p>","DOI":"10.3389\/fendo.2026.1883214","type":"journal-article","created":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:24:08Z","timestamp":1786595048000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dipeptidyl peptidase-4 inhibitors suppress myofibroblastic differentiation and hyaluronan synthesis in Graves\u2019 orbitopathy fibroblasts"],"prefix":"10.3389","volume":"17","author":[{"given":"Chih-Wei","family":"Shih","sequence":"first","affiliation":[{"name":"Graduate Institute of Clinical Medicine, National Taiwan University College of Medicine","place":["Taipei, Taiwan"]},{"name":"Department of Ophthalmology, Zhongxing Branch, Taipei City Hospital","place":["Taipei, Taiwan"]},{"name":"Department of Ophthalmology, Good Will Clinic","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Feng-Chiao","family":"Tsai","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital","place":["Taipei, Taiwan"]},{"name":"Department of Pharmacology, National Taiwan University College of Medicine","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shyang-Rong","family":"Shih","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital","place":["Taipei, Taiwan"]},{"name":"Department of Internal Medicine, National Taiwan University College of Medicine","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shu-Lang","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, National Taiwan University Hospital","place":["Taipei, Taiwan"]},{"name":"Department of Ophthalmology, National Taiwan University College of Medicine","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"I","family":"Chu","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, National Taiwan University Hospital","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tang-Meng","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, National Taiwan University College of Medicine","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neng-Li","family":"Liao","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, National Taiwan University College of Medicine","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Hsuan","family":"Wei","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, National Taiwan University Hospital","place":["Taipei, Taiwan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/cen.14296","article-title":"Prevalence of thyroid eye disease in Graves' disease: a meta-analysis and systematic review","volume":"93","author":"Chin","year":"2020","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2014.0475","article-title":"Role of the underlying thyroid disease on the phenotype of Graves' orbitopathy in a tertiary referral center","volume":"25","author":"Leo","year":"2015","journal-title":"Thyroid"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1001\/jamaophthalmol.2018.0806","article-title":"Association of T and B cells infiltrating orbital tissues with clinical features of Graves orbitopathy","volume":"136","author":"Rotondo Dottore","year":"2018","journal-title":"JAMA Ophthalmol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2022.101620","article-title":"Pathophysiology of thyroid-associated orbitopathy","volume":"37","author":"Lee","year":"2023","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1038\/s41574-024-01016-5","article-title":"Graves disease: latest understanding of pathogenesis and treatment options","volume":"20","author":"Lanzolla","year":"2024","journal-title":"Nat Rev Endocrinol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(25)00066-X","article-title":"Thyroid eye disease (Graves' orbitopathy): clinical presentation, epidemiology, pathogenesis, and management","volume":"13","author":"Wiersinga","year":"2025","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-21-0479","article-title":"The 2021 European Group on Graves' orbitopathy (EUGOGO) clinical practice guidelines for the medical management of Graves' orbitopathy","volume":"185","author":"Bartalena","year":"2021","journal-title":"Eur J Endocrinol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1155\/2015\/249125","article-title":"Graves' ophthalmopathy: VISA versus EUGOGO classification, assessment, and management","volume":"2015","author":"Barrio-Barrio","year":"2015","journal-title":"J Ophthalmol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-025-02790-3","article-title":"Markers of fibrosis in orbital tissues from patients graves' orbitopathy: a retrospective cohort study","volume":"49","author":"Dottore","year":"2025","journal-title":"J Endocrinol Invest"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2022.0251","article-title":"Management of thyroid eye disease: a consensus statement by the American Thyroid Association and the European Thyroid Association","volume":"32","author":"Burch","year":"2022","journal-title":"Thyroid"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3390\/jcm14155528","article-title":"Redefining treatment paradigms in thyroid eye disease: current and future therapeutic strategies","volume":"14","author":"Ciarmatori","year":"2025","journal-title":"J Clin Med"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1089\/thy.2023.0656","article-title":"Long-term efficacy of teprotumumab in thyroid eye disease: follow-up outcomes in three clinical trials","volume":"34","author":"Kahaly","year":"2024","journal-title":"Thyroid"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1097\/WNO.0000000000001994","article-title":"Real-world experience with teprotumumab in patients with dysthyroid optic neuropathy","volume":"44","author":"Tamhankar","year":"2024","journal-title":"J Neuroophthalmol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1177\/25158414211027760","article-title":"Updates on the understanding and management of thyroid eye disease","volume":"13","author":"Men","year":"2021","journal-title":"Ther Adv Ophthalmol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1159\/000356042","article-title":"Graves' orbitopathy: imperfect treatments for a rare disease","volume":"2","author":"Bartalena","year":"2013","journal-title":"Eur Thyroid J"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2025.1480195","article-title":"Teprotumumab in the management of thyroid eye disease mechanistic insights and adverse reactions: a comprehensive review","volume":"16","author":"Xu","year":"2025","journal-title":"Front Endocrinol (Lausanne)"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1080\/713609354","article-title":"Dipeptidyl-peptidase IV from bench to bedside: an update on structural properties, functions, and clinical aspects of the enzyme DPP IV","volume":"40","author":"Lambeir","year":"2003","journal-title":"Crit Rev Clin Lab Sci"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2022.830863","article-title":"Emerging role of dipeptidyl peptidase-4 in autoimmune disease","volume":"13","author":"Huang","year":"2022","journal-title":"Front Immunol"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1080\/07853890.2023.2226910","article-title":"The serum concentration and activity of DPP4 is positively related with the severity of hyperthyroidism in patients with Graves' disease","volume":"55","author":"Chang","year":"2023","journal-title":"Ann Med"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1177\/03000605221112031","article-title":"Assessment of serum dipeptidyl peptidase-IV levels in autoimmune thyroid disease","volume":"50","author":"Zhang","year":"2022","journal-title":"J Int Med Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.2337\/db13-1029","article-title":"Linagliptin-mediated DPP-4 inhibition ameliorates kidney fibrosis in streptozotocin-induced diabetic mice by inhibiting endothelial-to-mesenchymal transition in a therapeutic regimen","volume":"63","author":"Kanasaki","year":"2014","journal-title":"Diabetes"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1007\/s00535-013-0783-4","article-title":"Dipeptidyl peptidase-4 inhibitor attenuates hepatic fibrosis via suppression of activated hepatic stellate cell in rats","volume":"49","author":"Kaji","year":"2014","journal-title":"J Gastroenterol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacbts.2021.04.006","article-title":"Linagliptin, a xanthine-based dipeptidyl peptidase-4 inhibitor, ameliorates experimental autoimmune myocarditis","volume":"6","author":"Shiheido-Watanabe","year":"2021","journal-title":"JACC Basic Transl Sci"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1002\/art.41058","article-title":"Dipeptidylpeptidase 4 as a marker of activated fibroblasts and a potential target for the treatment of fibrosis in systemic sclerosis","volume":"72","author":"Soare","year":"2020","journal-title":"Arthritis Rheumatol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.3904\/kjim.2015.30.6.759","article-title":"Role of dipeptidyl peptidase-4 inhibitors in new-onset diabetes after transplantation","volume":"30","author":"Lim","year":"2015","journal-title":"Korean J Intern Med"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.64.10.2","article-title":"DPP-4 inhibitors attenuate fibrosis after glaucoma filtering surgery by suppressing the TGF-\u03b2\/Smad signaling pathway","volume":"64","author":"Yoshida","year":"2023","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B27","doi-asserted-by":"publisher","first-page":"2477","DOI":"10.1016\/j.jid.2024.03.020","article-title":"Dipeptidyl peptidase-4-mediated fibronectin processing evokes a profibrotic extracellular matrix","volume":"144","author":"Zeyer","year":"2024","journal-title":"J Invest Dermatol"},{"key":"B28","doi-asserted-by":"publisher","first-page":"1597","DOI":"10.1016\/j.jid.2021.10.025","article-title":"Skin fibrosis and recovery is dependent on Wnt activation via DPP4","volume":"142","author":"Jussila","year":"2022","journal-title":"J Invest Dermatol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1111\/bph.16236","article-title":"Therapeutic targets of fibrosis: translational advances and current challenges","volume":"180","author":"De Blasio","year":"2023","journal-title":"Br J Pharmacol"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1111\/bph.15967","article-title":"Targeting cluster of differentiation 26 \/ dipeptidyl peptidase 4 (CD26\/DPP4) in organ fibrosis","volume":"180","author":"Ohm","year":"2023","journal-title":"Br J Pharmacol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/S0002-9440(10)63488-8","article-title":"Thy-1 expression in human fibroblast subsets defines myofibroblastic or lipofibroblastic phenotypes","volume":"163","author":"Koumas","year":"2003","journal-title":"Am J Pathol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1002\/advs.202511404","article-title":"PDGFR\u03b1(+)DPP4(+) fibroblasts-macrophage crosstalk induces orbital fibrosis in treatment-resistant thyroid eye disease via the GAS6-AXL pathway","volume":"12","author":"Cheng","year":"2025","journal-title":"Adv Sci (Weinh)"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0307922","article-title":"Dipeptidyl peptidase 4 inhibitor sitagliptin decreases myocardial fibrosis and modulates myocardial insulin signaling in a swine model of chronic myocardial ischemia","volume":"19","author":"Harris","year":"2024","journal-title":"PloS One"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1007\/s12325-025-03257-w","article-title":"GLP-1 receptor agonists, DPP-4 inhibitors and the skin-diabetes meets dermatology: a brief narrative review","volume":"42","author":"Pantazopoulos","year":"2025","journal-title":"Adv Ther"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1152\/ajpcell.00451.2009","article-title":"Novel anti-adipogenic activity produced by human fibroblasts","volume":"299","author":"Lehmann","year":"2010","journal-title":"Am J Physiol Cell Physiol"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.3390\/ijms242216101","article-title":"Dipeptidyl peptidase 4 stimulation induces adipogenesis-related gene expression of adipose stromal cells","volume":"24","author":"Lai","year":"2023","journal-title":"Int J Mol Sci"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1038\/srep23074","article-title":"Metabolic role of dipeptidyl peptidase 4 (DPP4) in primary human (pre)adipocytes","volume":"6","author":"Zille\u00dfen","year":"2016","journal-title":"Sci Rep"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1167\/iovs.13-12741","article-title":"Orbital fibroblasts from thyroid eye disease patients differ in proliferative and adipogenic responses depending on disease subtype","volume":"54","author":"Kuriyan","year":"2013","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/j.1445-5994.2004.00662.x","article-title":"Thyroid-associated ophthalmopathy: a practical guide to classification, natural history and management","volume":"34","author":"El-Kaissi","year":"2004","journal-title":"Intern Med J"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-1299","article-title":"Adipose tissue depot-specific differences in the regulation of hyaluronan production of relevance to Graves' orbitopathy","volume":"97","author":"Zhang","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1155\/2019\/7453260","article-title":"Immunological aspects of Graves' ophthalmopathy","volume":"2019","author":"\u0141acheta","year":"2019","journal-title":"BioMed Res Int"},{"key":"B42","doi-asserted-by":"publisher","first-page":"9622","DOI":"10.1038\/s41598-019-46075-1","article-title":"Macrophages promote a profibrotic phenotype in orbital fibroblasts through increased hyaluronic acid production and cell contractility","volume":"9","author":"Yang","year":"2019","journal-title":"Sci Rep"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1097\/HC9.0000000000000083","article-title":"Hyaluronan in liver fibrosis: basic mechanisms, clinical implications, and therapeutic targets","volume":"7","author":"Kim","year":"2023","journal-title":"Hepatol Commun"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.3390\/ijms25063288","article-title":"The role of fibrogenesis and extracellular matrix proteins in the pathogenesis of Graves' ophthalmopathy","volume":"25","author":"Chiu","year":"2024","journal-title":"Int J Mol Sci"}],"container-title":["Frontiers in Endocrinology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1883214\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,13]],"date-time":"2026-08-13T04:24:09Z","timestamp":1786595049000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fendo.2026.1883214\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,13]]},"references-count":44,"alternative-id":["10.3389\/fendo.2026.1883214"],"URL":"https:\/\/doi.org\/10.3389\/fendo.2026.1883214","relation":{},"ISSN":["1664-2392"],"issn-type":[{"value":"1664-2392","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,13]]},"article-number":"1883214"}}