{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T18:01:33Z","timestamp":1772215293417,"version":"3.50.1"},"reference-count":64,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T00:00:00Z","timestamp":1772150400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012550","name":"Ministry of Innovation and Technology of Hungary from the National Research, Development and Innovation Fund","doi-asserted-by":"publisher","award":["TKP2021-EGA-24"],"award-info":[{"award-number":["TKP2021-EGA-24"]}],"id":[{"id":"10.13039\/501100012550","id-type":"DOI","asserted-by":"publisher"}]},{"name":"National Research, Development and Innovation Fund of Hungary","award":["TAGE 2024\u20141.2.3-HU-RIZONT-2024-00056"],"award-info":[{"award-number":["TAGE 2024\u20141.2.3-HU-RIZONT-2024-00056"]}]},{"DOI":"10.13039\/501100003825","name":"Hungarian Academy of Sciences","doi-asserted-by":"publisher","award":["LP2021-3\/2021"],"award-info":[{"award-number":["LP2021-3\/2021"]}],"id":[{"id":"10.13039\/501100003825","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Pharmaceuticals"],"abstract":"<jats:p>Background\/Objectives: Diabetes mellitus (DM) is associated with a doubled prevalence of elevated intraocular pressure (IOP) caused by trabecular meshwork (TM) dysfunction. Chronic hyperglycaemia leads to oxidative stress and fibrotic remodeling of the TM. We previously identified the Sigma-1 receptor (S1R) as a novel anti-fibrotic target by demonstrating that its agonist, fluvoxamine (FLU), is protective in diabetes-related renal fibrosis. Here, we investigate its potential to mitigate ocular fibrosis. Methods: First, we wanted to verify in different in vivo models (high-fat diet\/streptozotocin (HFD\/STZ) rats, db\/db mice) that type 2 DM (T2DM) leads to fibrotic remodeling of the TM. Then, in vitro, we assessed the effect of FLU (15 \u00b5M) on hyperglycaemia-induced (HG, 25 \u00b5M) fibrosis, oxidative stress and endogenous nitric oxide (NO) production. Results: In T2DM models, excessive accumulation of collagen, \u03b1-smooth muscle actin (\u03b1SMA), fibronectin (Fn) and F-actin was observed in the eyes. Ocular fibrosis was accompanied by IOP elevation (13.7 vs. 18.7 mmHg) in db\/db mice. In human TM cells (HTM5), FLU decreased HG-induced cell proliferation (14% vs. 24%) and upregulated S1R protein expression. Furthermore, FLU suppressed the expressions of key fibrotic elements, including transforming growth factor-\u03b22 (TGF-\u03b22) by 37%, Fn by 49%, collagen type 1 (COL1A1) and type 4 (COL4A1) by 24% and 45%, respectively. FLU also reversed HG-induced F-actin accumulation by 39% and enhanced intracellular NO levels by 34%. Crucially, FLU decreased ROS generation by half, demonstrating its protective effect against HG-induced oxidative stress. Conclusions: These findings highlight the potential of S1R activation as a promising therapeutic target to alleviate hyperglycaemia-induced injury to the TM by modulating multiple molecular pathways.<\/jats:p>","DOI":"10.3390\/ph19030385","type":"journal-article","created":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T17:05:16Z","timestamp":1772211916000},"page":"385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Sigma-1 Receptor Agonist Fluvoxamine Is Protective in Hyperglycaemia-Induced Dysfunction of Trabecular Meshwork Cells"],"prefix":"10.3390","volume":"19","author":[{"given":"Alexandra","family":"Rozsahegyi","sequence":"first","affiliation":[{"name":"MTA-SE Lend\u00fclet \u201cMomentum\u201d Diabetes Research Group, 1083 Budapest, Hungary"},{"name":"Pediatric Center, MTA Center of Excellence, Semmelweis University, 1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0837-2178","authenticated-orcid":false,"given":"Marcell","family":"Cserhalmi","sequence":"additional","affiliation":[{"name":"MTA-SE Lend\u00fclet \u201cMomentum\u201d Diabetes Research Group, 1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3618-6690","authenticated-orcid":false,"given":"Timea","family":"Medveczki","sequence":"additional","affiliation":[{"name":"MTA-SE Lend\u00fclet \u201cMomentum\u201d Diabetes Research Group, 1083 Budapest, Hungary"},{"name":"Pediatric Center, MTA Center of Excellence, Semmelweis University, 1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zsuzsanna","family":"Buzogany","sequence":"additional","affiliation":[{"name":"MTA-SE Lend\u00fclet \u201cMomentum\u201d Diabetes Research Group, 1083 Budapest, Hungary"},{"name":"Pediatric Center, MTA Center of Excellence, Semmelweis University, 1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7779-226X","authenticated-orcid":false,"given":"Eva","family":"Ruisanchez","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"},{"name":"HUN-REN-SU Cerebrovascular and Neurocognitive Disorders Research Group, 1094 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4634-2140","authenticated-orcid":false,"given":"Andras","family":"Budai","sequence":"additional","affiliation":[{"name":"Department of Pathology, Forensic and Insurance Medicine, Semmelweis University, 1091 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5636-284X","authenticated-orcid":false,"given":"Balazs","family":"Besztercei","sequence":"additional","affiliation":[{"name":"Institute of Translational Medicine, Semmelweis University, 1094 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7321-9861","authenticated-orcid":false,"given":"Attila J","family":"Szabo","sequence":"additional","affiliation":[{"name":"Pediatric Center, MTA Center of Excellence, Semmelweis University, 1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6388-4021","authenticated-orcid":false,"given":"Judit","family":"Hodrea","sequence":"additional","affiliation":[{"name":"MTA-SE Lend\u00fclet \u201cMomentum\u201d Diabetes Research Group, 1083 Budapest, Hungary"},{"name":"Pediatric Center, MTA Center of Excellence, Semmelweis University, 1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0210-153X","authenticated-orcid":false,"given":"Andrea","family":"Fekete","sequence":"additional","affiliation":[{"name":"MTA-SE Lend\u00fclet \u201cMomentum\u201d Diabetes Research Group, 1083 Budapest, Hungary"},{"name":"Pediatric Center, MTA Center of Excellence, Semmelweis University, 1083 Budapest, Hungary"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1016\/j.diabres.2009.10.007","article-title":"Global estimates of the prevalence of diabetes for 2010 and 2030","volume":"87","author":"Shaw","year":"2010","journal-title":"Diabetes Res. 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