{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T18:44:12Z","timestamp":1776278652876,"version":"3.50.1"},"reference-count":69,"publisher":"Public Library of Science (PLoS)","issue":"4","license":[{"start":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T00:00:00Z","timestamp":1776211200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Nature Science Foundation of Shanxi Province","award":["202103021224345"],"award-info":[{"award-number":["202103021224345"]}]},{"DOI":"10.13039\/501100004480","name":"Natural Science Foundation of Shanxi Province","doi-asserted-by":"publisher","award":["202103021223402"],"award-info":[{"award-number":["202103021223402"]}],"id":[{"id":"10.13039\/501100004480","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017949","name":"Health Commission of Shanxi Province","doi-asserted-by":"publisher","award":["2020004"],"award-info":[{"award-number":["2020004"]}],"id":[{"id":"10.13039\/100017949","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017949","name":"Health Commission of Shanxi Province","doi-asserted-by":"publisher","award":["2022-203"],"award-info":[{"award-number":["2022-203"]}],"id":[{"id":"10.13039\/100017949","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Shanxi Bethune Hospital Foundation","award":["2021RC005"],"award-info":[{"award-number":["2021RC005"]}]},{"name":"Open Project of Shanxi Key Laboratory of Ophthalmology","award":["2023SXKLOS01"],"award-info":[{"award-number":["2023SXKLOS01"]}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS One"],"abstract":"<jats:p>\n                    Glaucoma, a leading global cause of blindness, is characterized by progressive retinal neuronal loss. NOP2\/Sun RNA methyltransferase 4 (NSUN4), a writer of 5-methylcytosine (m5C) RNA modifications, has established roles in methylation and mitoribosome assembly, yet its function in retinal cell survival remains unexplored. In this study, integrated methylated RNA immunoprecipitation sequencing (MeRIP-seq) and RNA-seq analysis in an NMDA-induced retinal injury model revealed widespread mRNA hypomethylation enriched in the Sonic Hedgehog (SHH) signaling pathway, accompanied by significant downregulation of\n                    <jats:italic>Nsun4<\/jats:italic>\n                    . To investigate the underlying mechanisms, we utilized the R28 retinal cell line, a widely accepted model for studying retinal neuroprotection. In glutamate-stimulated R28 cells, NSUN4 overexpression mitigated excitotoxic injury, attenuating Ca\u00b2\u2009\u207a\u2009overload, mitochondrial dysfunction, and apoptosis. Mechanistically, NSUN4 enhanced m5C methylation on key SHH pathway transcripts (\n                    <jats:italic>Shh, Gli1, and Gli2<\/jats:italic>\n                    ). Crucially, the neuroprotective effect of NSUN4 was abolished upon pharmacological inhibition of the SHH pathway using Vismodegib, confirming that pathway activation is essential for NSUN4-mediated protection. Clinically,\n                    <jats:italic>NSUN4<\/jats:italic>\n                    levels were significantly reduced in the aqueous humor of patients with primary open-angle glaucoma compared to controls. Together, these findings establish NSUN4 as an m5C-dependent activator of the SHH pathway that protects retinal cells against excitotoxic injury, nominating it as a novel candidate for glaucoma neuroprotection.\n                  <\/jats:p>","DOI":"10.1371\/journal.pone.0347414","type":"journal-article","created":{"date-parts":[[2026,4,15]],"date-time":"2026-04-15T17:46:31Z","timestamp":1776275191000},"page":"e0347414","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":0,"title":["NSUN4-mediated m5C RNA methylation protects retinal cells against excitotoxic injury via the SHH signaling pathway"],"prefix":"10.1371","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6538-7558","authenticated-orcid":true,"given":"Yahong","family":"Li","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dian","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chao","family":"Geng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruihua","family":"Wei","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yajian","family":"Duan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2026,4,15]]},"reference":[{"key":"pone.0347414.ref001","doi-asserted-by":"crossref","first-page":"493","DOI":"10.1016\/j.mcna.2021.01.004","article-title":"Glaucoma","volume":"105","author":"JM 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