{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T22:01:41Z","timestamp":1791928901095,"version":"4.3.4"},"reference-count":53,"publisher":"Association for Research in Vision and Ophthalmology (ARVO)","issue":"15","license":[{"start":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T00:00:00Z","timestamp":1764892800000},"content-version":"unspecified","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Invest. Ophthalmol. Vis. Sci."],"published-print":{"date-parts":[[2025,12,5]]},"DOI":"10.1167\/iovs.66.15.22","type":"journal-article","created":{"date-parts":[[2025,12,5]],"date-time":"2025-12-05T14:30:37Z","timestamp":1764945037000},"page":"22","source":"Crossref","is-referenced-by-count":5,"title":["Sphingomyelin Synthase 2 Deletion Mitigates Oxidative Stress-Induced NF-\u03baB Activation via Lipid Metabolic Reprogramming in Dry Eye Disease"],"prefix":"10.1167","volume":"66","author":[{"given":"Yiteng","family":"Lu","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xichen","family":"Wan","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Han","family":"Ye","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yirou","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingrui","family":"Cheng","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xingyu","family":"Zhu","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuyu","family":"Cao","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyuan","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qingye","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Runhan","family":"Shi","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qihua","family":"Le","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xujiao","family":"Zhou","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaxu","family":"Hong","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Eye & ENT Hospital, State Key Laboratory of Brain Function and Disorders, MOE Frontiers Center for Brain Science, Fudan University, Shanghai, China"},{"name":"NHC Key laboratory of Myopia and Related Eye Diseases, Shanghai, China"},{"name":"Shanghai Key Laboratory of Rare Disease Gene Editing and Cell Therapy; Shanghai Engineering Research Center of Synthetic Immunology, Shanghai, China"},{"name":"Department of Ophthalmology, Children's Hospital of Fudan University, National Pediatric Medical Center of China, Shanghai, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"27","reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"276","DOI":"10.1016\/j.jtos.2017.05.008","article-title":"TFOS DEWS II definition and classification report","volume":"15","author":"Craig","year":"2017","journal-title":"Ocul Surf"},{"key":"bib2","doi-asserted-by":"crossref","DOI":"10.3390\/ijms22116114","article-title":"Cascade of inflammatory, fibrotic processes, and stress-induced senescence in chronic GVHD-related dry eye disease","volume":"22","author":"Ogawa","year":"2021","journal-title":"Int J Mol Sci"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1016\/j.jtos.2017.05.003","article-title":"TFOS DEWS II epidemiology report","volume":"15","author":"Stapleton","year":"2017","journal-title":"Ocul Surf"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"723","DOI":"10.1111\/aos.15105","article-title":"Video display terminal use and dry eye: preventive measures and future perspectives","volume":"100","author":"Kam\u00f8y","year":"2022","journal-title":"Acta Ophthalmol"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"2615","DOI":"10.1007\/s10565-023-09791-z","article-title":"PM(2.5) exposure increases dry eye disease risks through corneal epithelial inflammation and mitochondrial dysfunctions","volume":"39","author":"Yu","year":"2023","journal-title":"Cell Biol Toxicol"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"e0271267","DOI":"10.1371\/journal.pone.0271267","article-title":"Identified risk factors for dry eye syndrome: a systematic review and meta-analysis","volume":"17","author":"Qian","year":"2022","journal-title":"PLoS One"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"575","DOI":"10.1016\/j.jtos.2017.05.006","article-title":"TFOS DEWS II management and therapy report","volume":"15","author":"Jones","year":"2017","journal-title":"Ocul Surf"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"1606","DOI":"10.1136\/bjo-2022-321246","article-title":"Relationship between dry eye symptoms and quality of life: associations and mediation analysis","volume":"107","author":"Lim","year":"2023","journal-title":"Br J Ophthalmol"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1016\/j.jtos.2017.05.011","article-title":"TFOS DEWS II pathophysiology report","volume":"15","author":"Bron","year":"2017","journal-title":"Ocul Surf"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1001\/jamaophthalmol.2022.4394","article-title":"Prevalence and incidence of dry eye and meibomian gland dysfunction in the United States: a systematic review and meta-analysis","volume":"140","author":"McCann","year":"2022","journal-title":"JAMA Ophthalmol"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"3174","DOI":"10.1177\/11206721221091375","article-title":"Dry eye in Sj\u00f6gren's syndrome\u2014characteristics and therapy","volume":"32","author":"Caban","year":"2022","journal-title":"Eur J Ophthalmol"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"155081","DOI":"10.1016\/j.phymed.2023.155081","article-title":"Berberine ameliorate inflammation and apoptosis via modulating PI3K\/AKT\/NF?B and MAPK pathway on dry eye","volume":"121","author":"Han","year":"2023","journal-title":"Phytomedicine"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"109007","DOI":"10.1016\/j.exer.2022.109007","article-title":"Immune regulation of the ocular surface","volume":"218","author":"Chen","year":"2022","journal-title":"Exp Eye Res"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"463","DOI":"10.1007\/s10792-022-02443-x","article-title":"Tear film instability is associated with weakened colocalization between occludin and MUC5AC in scopolamine-induced dry eye disease (DED) rats","volume":"43","author":"Xu","year":"2023","journal-title":"Int Ophthalmol"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"931","DOI":"10.1097\/OPX.0000000000000664","article-title":"Altered mucin and glycoprotein expression in dry eye disease","volume":"92","author":"Stephens","year":"2015","journal-title":"Optom Vis Sci"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1038\/cr.2010.178","article-title":"Crosstalk of reactive oxygen species and NF-?B signaling","volume":"21","author":"Morgan","year":"2011","journal-title":"Cell Res"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"1256","DOI":"10.4103\/IJO.IJO_2791_22","article-title":"Benzalkonium chloride-induced dry eye disease animal models: current understanding and potential for translational research","volume":"71","author":"Thacker","year":"2023","journal-title":"Indian J Ophthalmol"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"S20","DOI":"10.1016\/j.ophtha.2017.05.031","article-title":"Meibomian gland disease: the role of gland dysfunction in dry eye disease","volume":"124","author":"Chhadva","year":"2017","journal-title":"Ophthalmology"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.jtos.2021.12.011","article-title":"Characterization of the thickness of the tear film lipid layer in meibomian gland dysfunction using high resolution optical microscopy","volume":"24","author":"Bai","year":"2022","journal-title":"Ocul Surf"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"4782","DOI":"10.3390\/ijms25094782","article-title":"Meibum lipidomic analysis in evaporative dry eye subjects","volume":"25","author":"Garcia-Queiruga","year":"2024","journal-title":"Int J Mol Sci"},{"key":"bib21","doi-asserted-by":"publisher","first-page":"90","DOI":"10.1016\/j.coph.2019.02.004","article-title":"Purinergic receptors and the inflammatory response mediated by lipids","volume":"47","author":"Alarc\u00f3n-Vila","year":"2019","journal-title":"Curr Opin Pharmacol"},{"key":"bib22","doi-asserted-by":"publisher","first-page":"101182","DOI":"10.1016\/j.plipres.2022.101182","article-title":"Lipid-protein interactions regulating the canonical and the non-canonical NLRP3 inflammasome","volume":"87","author":"Pizzuto","year":"2022","journal-title":"Prog Lipid Res"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1038\/s41573-022-00470-y","article-title":"Drugging the efferocytosis process: concepts and opportunities","volume":"21","author":"Mehrotra","year":"2022","journal-title":"Nat Rev Drug Discov"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"1143","DOI":"10.3109\/02713683.2015.1098707","article-title":"Expression of lipid peroxidation markers in the tear film and ocular surface of patients with non-sjogren syndrome: potential biomarkers for dry eye disease","volume":"41","author":"Choi","year":"2016","journal-title":"Curr Eye Res"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/S0009-3084(99)00072-9","article-title":"Sphingomyelin: biophysical aspects","volume":"102","author":"Barenholz","year":"1999","journal-title":"Chem Phys Lipids"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"424","DOI":"10.1016\/j.plipres.2013.05.001","article-title":"Biological functions of sphingomyelins","volume":"52","author":"Slotte","year":"2013","journal-title":"Prog Lipid Res"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"202","DOI":"10.1016\/j.bbrc.2016.11.041","article-title":"Possible roles of long-chain sphingomyelines and sphingomyelin synthase 2 in mouse macrophage inflammatory response","volume":"482","author":"Sakamoto","year":"2017","journal-title":"Biochem Biophys Res Commun"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"158549","DOI":"10.1016\/j.bbalip.2019.158549","article-title":"Sphingomyelin synthase activity affects TRIF-dependent signaling of Toll-like receptor 4 in cells stimulated with lipopolysaccharide","volume":"1865","author":"Prymas","year":"2020","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"318","DOI":"10.1016\/j.jtos.2018.12.006","article-title":"Clinical signs of meibomian gland dysfunction (MGD) are associated with changes in meibum sphingolipid composition","volume":"17","author":"Paranjpe","year":"2019","journal-title":"Ocul Surf"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"87","DOI":"10.1016\/j.jtos.2021.11.011","article-title":"Meibum sphingolipid composition is altered in individuals with meibomian gland dysfunction-a side by side comparison of meibum and tear sphingolipids","volume":"23","author":"Galor","year":"2022","journal-title":"Ocul Surf"},{"key":"bib31","doi-asserted-by":"publisher","first-page":"158728","DOI":"10.1016\/j.bbalip.2020.158728","article-title":"Lipidomic analysis of epithelial corneal cells following hyperosmolarity and benzalkonium chloride exposure: new insights in dry eye disease","volume":"1865","author":"Magny","year":"2020","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1016\/j.jtos.2021.12.013","article-title":"In situ metabolic profile and spatial distribution of ocular tissues: new insights into dry eye disease","volume":"24","author":"Chen","year":"2022","journal-title":"Ocul Surf"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"3330","DOI":"10.1167\/iovs.05-0756","article-title":"Identification and comparison of the polar phospholipids in normal and dry eye rabbit tears by MALDI-TOF mass spectrometry","volume":"47","author":"Ham","year":"2006","journal-title":"Invest Ophthalmol Vis Sci"},{"key":"bib34","doi-asserted-by":"publisher","first-page":"158898","DOI":"10.1016\/j.bbalip.2021.158898","article-title":"Effect of liver total sphingomyelin synthase deficiency on plasma lipid metabolism","volume":"1866","author":"Li","year":"2021","journal-title":"Biochim Biophys Acta Mol Cell Biol Lipids"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"249","DOI":"10.1084\/jem.20041685","article-title":"Role of membrane sphingomyelin and ceramide in platform formation for Fas-mediated apoptosis","volume":"202","author":"Miyaji","year":"2005","journal-title":"J Exp Med"},{"key":"bib36","doi-asserted-by":"publisher","first-page":"1519","DOI":"10.1161\/ATVBAHA.108.168682","article-title":"Sphingomyelin synthase 2 deficiency attenuates NFkappaB activation","volume":"28","author":"Hailemariam","year":"2008","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"295","DOI":"10.1161\/CIRCRESAHA.109.194613","article-title":"Macrophage sphingomyelin synthase 2 deficiency decreases atherosclerosis in mice","volume":"105","author":"Liu","year":"2009","journal-title":"Circ Res"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"e012885","DOI":"10.1161\/JAHA.119.012885","article-title":"Sphingomyelin synthase 2 inhibition ameliorates cerebral ischemic reperfusion injury through reducing the recruitment of toll-like receptor 4 to lipid rafts","volume":"8","author":"Xue","year":"2019","journal-title":"J Am Heart Assoc"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"3301","DOI":"10.3892\/mmr.2016.5611","article-title":"Sphingomyelin synthase 2 affects CD14-associated induction of NF-?B by lipopolysaccharides in acute lung injury in mice","volume":"14","author":"Hu","year":"2016","journal-title":"Mol Med Rep"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"107960","DOI":"10.1016\/j.jbc.2024.107960","article-title":"Multiple activities of sphingomyelin synthase 2 generate saturated fatty acid- and\/or monounsaturated fatty acid-containing diacylglycerol","volume":"300","author":"Murakami","year":"2024","journal-title":"J Biol Chem"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1016\/j.apsb.2024.10.005","article-title":"Discovery of a novel thiophene carboxamide analogue as a highly potent and selective sphingomyelin synthase 2 inhibitor for dry eye disease therapy","volume":"15","author":"Yang","year":"2025","journal-title":"Acta Pharm Sin B"},{"key":"bib42","doi-asserted-by":"publisher","first-page":"757","DOI":"10.2147\/OPTH.S398843","article-title":"Validation of a modified national eye institute grading scale for corneal fluorescein staining","volume":"17","author":"Sall","year":"2023","journal-title":"Clin Ophthalmol"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"1717","DOI":"10.1007\/s00417-020-04647-2","article-title":"Inflammation and oxidative stress induced by lipid peroxidation metabolite 4-hydroxynonenal in human corneal epithelial cells","volume":"258","author":"Liu","year":"2020","journal-title":"Graefes Arch Clin Exp Ophthalmol"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"1086","DOI":"10.1111\/febs.17379","article-title":"Hypoxia-induced increase in sphingomyelin synthase 2 aggravates ischemic skeletal muscle inflammation","volume":"292","author":"Mizugaki","year":"2025","journal-title":"FEBS J"},{"key":"bib45","doi-asserted-by":"crossref","first-page":"241","DOI":"10.3892\/etm.2020.9371","article-title":"Lack of sphingomyelin synthase 2 reduces cerebral ischemia\/reperfusion injury by inhibiting microglial inflammation in mice","volume":"20","author":"Yang","year":"2020","journal-title":"Exp Ther Med"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"791","DOI":"10.1177\/0960327120969958","article-title":"Inhibition of sphingomyelin synthase 2 relieves hypoxia-induced cardiomyocyte injury by reinforcing Nrf2\/ARE activation via modulation of GSK-3\u00df","volume":"40","author":"Jin","year":"2021","journal-title":"Hum Exp Toxicol"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"276","DOI":"10.3390\/biom11020276","article-title":"Protective role of sphingomyelin in eye lens cell membrane model against oxidative stress","volume":"11","author":"Ravandeh","year":"2021","journal-title":"Biomolecules"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.ab.2016.10.021","article-title":"Assessment of lipid peroxidation by measuring malondialdehyde (MDA) and relatives in biological samples: analytical and biological challenges","volume":"524","author":"Tsikas","year":"2017","journal-title":"Anal Biochem"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"110119","DOI":"10.1016\/j.cellsig.2021.110119","article-title":"Role of ceramide\/sphingomyelin (SM) balance regulated through \"SM cycle\" in cancer","volume":"87","author":"Taniguchi","year":"2021","journal-title":"Cell Signal"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"75","DOI":"10.1016\/j.jare.2023.07.008","article-title":"Ceramide-1-phosphate alleviates high-altitude pulmonary edema by stabilizing circadian ARNTL-mediated mitochondrial dynamics","volume":"60","author":"Tian","year":"2024","journal-title":"J Adv Res"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"2050","DOI":"10.3390\/antiox11102050","article-title":"Sphingosine-1-phosphate alleviates irradiation induced salivary gland hypofunction through preserving endothelial cells and resident macrophages","volume":"11","author":"Yang","year":"2022","journal-title":"Antioxidants (Basel)"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1186\/s12944-020-01286-8","article-title":"Diacylglycerol-evoked activation of PKC and PKD isoforms in regulation of glucose and lipid metabolism: a review","volume":"19","author":"Kolczynska","year":"2020","journal-title":"Lipids Health Dis"},{"key":"bib53","doi-asserted-by":"publisher","first-page":"765","DOI":"10.1016\/0092-8674(92)90553-O","article-title":"TNF activates NF-kappa B by phosphatidylcholine-specific phospholipase C-induced \"acidic\" sphingomyelin breakdown","volume":"71","author":"Sch\u00fctze","year":"1992","journal-title":"Cell"}],"container-title":["Investigative Ophthalmology & Visual Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/iovs.arvojournals.org\/article.aspx?articleid=2811193","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T21:32:00Z","timestamp":1791927120000},"score":1,"resource":{"primary":{"URL":"https:\/\/iovs.arvojournals.org\/article.aspx?articleid=2811193"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,5]]},"references-count":53,"journal-issue":{"issue":"15","published-print":{"date-parts":[[2025,12,1]]}},"URL":"https:\/\/doi.org\/10.1167\/iovs.66.15.22","relation":{},"ISSN":["1552-5783"],"issn-type":[{"value":"1552-5783","type":"print"}],"subject":[],"published":{"date-parts":[[2025,12,5]]}}}