{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T12:08:16Z","timestamp":1778846896102,"version":"3.51.4"},"reference-count":72,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2026,5,9]],"date-time":"2026-05-09T00:00:00Z","timestamp":1778284800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["CIMB"],"abstract":"<jats:p>Background: Dry eye disease (DED) is a multifactorial ocular surface disorder characterized by tear film instability, inflammation, and neurosensory abnormalities. Current therapies remain limited by slow onset and suboptimal efficacy. Teriflunomide, an immunomodulatory agent approved for multiple sclerosis, has shown therapeutic potential in DED, but its multi-target mechanisms remain unclear. Methods: We employed an integrated computational and transcriptomic framework combining ADMET profiling, multi-dataset transcriptomic integration, and single-cell RNA sequencing (scRNA-seq) to identify disease-relevant targets. Candidate genes were further refined through molecular docking and 50 ns molecular dynamics (MD) simulations. The AetherCell virtual cell model was applied to evaluate both the concordance between target perturbation and drug-induced responses and the potential mechanistic roles of candidate targets. Results: Transcriptomic integration identified 16 consensus genes across heterogeneous DED models, which were further localized to disease-relevant epithelial and immune cell populations by scRNA-seq. Molecular simulations prioritized three core targets\u2014CTSS, STAT1, and PTGS1\u2014based on binding stability and affinity. AetherCell simulations demonstrated that perturbation of these targets not only recapitulated teriflunomide-induced transcriptional and pathway changes but also revealed their distinct mechanistic contributions, including epithelial barrier regulation (CTSS), microvascular and lipid homeostasis (PTGS1), and inflammation suppression coupled with tissue repair (STAT1). Conclusions: Teriflunomide exerts therapeutic effects in DED through coordinated multi-target regulation involving inflammation control, barrier restoration, and tissue repair. This study provides a rationale for novel therapeutic targets in dry eye disease, establishes a paradigm for applying virtual cell modeling to elucidate drug mechanisms, and offers a bioinformatics framework for validating drug repositioning outcomes.<\/jats:p>","DOI":"10.3390\/cimb48050492","type":"journal-article","created":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T10:33:21Z","timestamp":1778841201000},"page":"492","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Target Discovery and Systemic Mechanism Analysis of Teriflunomide for Dry Eye Disease"],"prefix":"10.3390","volume":"48","author":[{"ORCID":"https:\/\/orcid.org\/0009-0002-6644-6761","authenticated-orcid":false,"given":"Yang","family":"Chen","sequence":"first","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Weiran","family":"Lin","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Medical Neurobiology, Institute for Translational Brain Research, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Feng","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wenyuan","family":"Li","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3211-3726","authenticated-orcid":false,"given":"Lianhao","family":"Song","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou 510060, China"},{"name":"Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"102627","DOI":"10.1016\/j.clae.2026.102627","article-title":"Global Prevalence of Dry Eye: A Systematic Review and Meta-Analysis","volume":"49","author":"Xiao","year":"2025","journal-title":"Contact Lens Anterior Eye"},{"key":"ref_2","unstructured":"(2026, March 24). Dry Eye Disease Treatment Market Size and Share Analysis. Available online: https:\/\/www.delveinsight.com\/report-store\/dry-eye-disease-treatment-market."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1097\/ICO.0b013e3181f7f363","article-title":"The Economic Burden of Dry Eye Disease in the United States: A Decision Tree Analysis","volume":"30","author":"Yu","year":"2011","journal-title":"Cornea"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.jtos.2023.01.006","article-title":"The Work-Related Burden of Dry Eye","volume":"28","author":"Morthen","year":"2023","journal-title":"Ocul. Surf."},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Jiang, X., Xu, B., Xu, R., Wu, N., Tian, S., Peng, H., and Zhao, Y. (2026). A Comprehensive Analysis of Dry Eye Disease Clinical Trials (2000\u20132024): Research Trends and Gaps. Front. Pharmacol., 17.","DOI":"10.3389\/fphar.2026.1713433"},{"key":"ref_6","doi-asserted-by":"crossref","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":"ref_7","doi-asserted-by":"crossref","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":"ref_8","doi-asserted-by":"crossref","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":"ref_9","doi-asserted-by":"crossref","first-page":"631","DOI":"10.1016\/S0161-6420(99)00176-1","article-title":"Two Multicenter, Randomized Studies of the Efficacy and Safety of Cyclosporine Ophthalmic Emulsion in Moderate to Severe Dry Eye Disease. CsA Phase 3 Study Group","volume":"107","author":"Sall","year":"2000","journal-title":"Ophthalmology"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"967","DOI":"10.1016\/S0161-6420(00)00035-X","article-title":"Efficacy and Safety of Cyclosporin A Ophthalmic Emulsion in the Treatment of Moderate-to-Severe Dry Eye Disease: A Dose-Ranging, Randomized Trial. The Cyclosporin A Phase 2 Study Group","volume":"107","author":"Stevenson","year":"2000","journal-title":"Ophthalmology"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.ophtha.2013.09.015","article-title":"OPUS-1 Study Group. Lifitegrast Ophthalmic Solution 5.0% for Treatment of Dry Eye Disease: Results of the OPUS-1 Phase 3 Study","volume":"121","author":"Sheppard","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1293","DOI":"10.1056\/NEJMoa1014656","article-title":"Randomized Trial of Oral Teriflunomide for Relapsing Multiple Sclerosis","volume":"365","author":"Wolinsky","year":"2011","journal-title":"N. Engl. J. Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3148","DOI":"10.1021\/jm301848w","article-title":"On Dihydroorotate Dehydrogenases and Their Inhibitors and Uses","volume":"56","author":"Vidalain","year":"2013","journal-title":"J. Med. Chem."},{"key":"ref_14","unstructured":"Li, W., Chen, Y., Peng, Z., Xiang, L., Wang, D., and Xie, Z. (2026). AetherCell: A Generative Engine for Virtual Cell Perturbation and in Vivo Drug Discovery. bioRxiv, bioRxiv:2026.03.13.710968."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1006\/clim.1999.4777","article-title":"Mechanism of Action for Leflunomide in Rheumatoid Arthritis","volume":"93","author":"Fox","year":"1999","journal-title":"Clin. Immunol."},{"key":"ref_16","first-page":"257","article-title":"A Mouse Dry Eye Model Induced by Topical Administration of Benzalkonium Chloride","volume":"17","author":"Lin","year":"2011","journal-title":"Mol. Vis."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1089\/jop.2020.0014","article-title":"Loteprednol Etabonate for the Treatment of Dry Eye Disease","volume":"36","author":"Beckman","year":"2020","journal-title":"J. Ocul. Pharmacol. Ther."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"659","DOI":"10.1007\/s40265-014-0212-x","article-title":"Teriflunomide and Its Mechanism of Action in Multiple Sclerosis","volume":"74","author":"Pachner","year":"2014","journal-title":"Drugs"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1136\/bjophthalmol-2015-307415","article-title":"Revisiting the Vicious Circle of Dry Eye Disease: A Focus on the Pathophysiology of Meibomian Gland Dysfunction","volume":"100","author":"Baudouin","year":"2016","journal-title":"Br. J. Ophthalmol."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Jones, J., Frenia, K., Gelman, J., Beatty, M., Zhou, M., Ma, L., Pieramici, S., Eger, N., Dhaliwal, D., and Labriola, L.T. (2025). Translating Biomarker Discovery: From Bench to Bedside in Dry Eye Disease. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms26178556"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"W422","DOI":"10.1093\/nar\/gkae236","article-title":"ADMETlab 3.0: An Updated Comprehensive Online ADMET Prediction Platform Enhanced with Broader Coverage, Improved Performance, API Functionality and Decision Support","volume":"52","author":"Fu","year":"2024","journal-title":"Nucleic Acids Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1038\/s41576-019-0093-7","article-title":"Integrative Single-Cell Analysis","volume":"20","author":"Stuart","year":"2019","journal-title":"Nat. Rev. Genet."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"455","DOI":"10.1002\/jcc.21334","article-title":"AutoDock Vina: Improving the Speed and Accuracy of Docking with a New Scoring Function, Efficient Optimization and Multithreading","volume":"31","author":"Trott","year":"2010","journal-title":"J. Comput. Chem."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/j.softx.2015.06.001","article-title":"GROMACS: High Performance Molecular Simulations through Multi-Level Parallelism from Laptops to Supercomputers","volume":"1\u20132","author":"Abraham","year":"2015","journal-title":"SoftwareX"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1093\/nar\/30.1.207","article-title":"Gene Expression Omnibus: NCBI Gene Expression and Hybridization Array Data Repository","volume":"30","author":"Edgar","year":"2002","journal-title":"Nucleic Acids Res."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"550","DOI":"10.1186\/s13059-014-0550-8","article-title":"Moderated Estimation of Fold Change and Dispersion for RNA-Seq Data with DESeq2","volume":"15","author":"Love","year":"2014","journal-title":"Genome Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1093\/bioinformatics\/bty895","article-title":"Heavy-Tailed Prior Distributions for Sequence Count Data: Removing the Noise and Preserving Large Differences","volume":"35","author":"Zhu","year":"2019","journal-title":"Bioinformatics"},{"key":"ref_28","unstructured":"Korotkevich, G., Sukhov, V., Budin, N., Shpak, B., Artyomov, M.N., and Sergushichev, A. (2021). Fast Gene Set Enrichment Analysis. biorxiv, biorxiv:060012."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Gene Ontology Consortium (2021). The Gene Ontology Resource: Enriching a GOld Mine. Nucleic Acids Res., 49, D325\u2013D334.","DOI":"10.1093\/nar\/gkaa1113"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1093\/nar\/28.1.27","article-title":"KEGG: Kyoto Encyclopedia of Genes and Genomes","volume":"28","author":"Kanehisa","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"W356","DOI":"10.1093\/nar\/gkx374","article-title":"PharmMapper 2017 Update: A Web Server for Potential Drug Target Identification with a Comprehensive Target Pharmacophore Database","volume":"45","author":"Wang","year":"2017","journal-title":"Nucleic Acids Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"W609","DOI":"10.1093\/nar\/gkq300","article-title":"PharmMapper Server: A Web Server for Potential Drug Target Identification Using Pharmacophore Mapping Approach","volume":"38","author":"Liu","year":"2010","journal-title":"Nucleic Acids Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: An R Package for Comparing Biological Themes among Gene Clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"D607","DOI":"10.1093\/nar\/gky1131","article-title":"STRING V11: Protein\u2013Protein Association Networks with Increased Coverage, Supporting Functional Discovery in Genome-Wide Experimental Datasets","volume":"47","author":"Szklarczyk","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"14049","DOI":"10.1038\/ncomms14049","article-title":"Massively Parallel Digital Transcriptional Profiling of Single Cells","volume":"8","author":"Zheng","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1038\/nbt.4096","article-title":"Integrating Single-Cell Transcriptomic Data across Different Conditions, Technologies, and Species","volume":"36","author":"Butler","year":"2018","journal-title":"Nat. Biotechnol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41592-019-0619-0","article-title":"Fast, Sensitive and Accurate Integration of Single-Cell Data with Harmony","volume":"16","author":"Korsunsky","year":"2019","journal-title":"Nat. Methods"},{"key":"ref_38","unstructured":"McInnes, L., Healy, J., and Melville, J. (2020). UMAP: Uniform Manifold Approximation and Projection for Dimension Reduction. arXiv."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"P10008","DOI":"10.1088\/1742-5468\/2008\/10\/P10008","article-title":"Fast Unfolding of Communities in Large Networks","volume":"2008","author":"Blondel","year":"2008","journal-title":"J. Stat. Mech."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1093\/nar\/28.1.235","article-title":"The Protein Data Bank","volume":"28","author":"Berman","year":"2000","journal-title":"Nucleic Acids Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"D1388","DOI":"10.1093\/nar\/gkaa971","article-title":"PubChem in 2021: New Data Content and Improved Web Interfaces","volume":"49","author":"Kim","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"2785","DOI":"10.1002\/jcc.21256","article-title":"AutoDock4 and AutoDockTools4: Automated Docking with Selective Receptor Flexibility","volume":"30","author":"Morris","year":"2009","journal-title":"J. Comput. Chem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1016\/j.febslet.2006.01.074","article-title":"Blind Docking of Drug-Sized Compounds to Proteins with up to a Thousand Residues","volume":"580","year":"2006","journal-title":"FEBS Lett."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1007\/s10822-013-9698-7","article-title":"Fragment-Based Shape Signatures: A New Tool for Virtual Screening and Drug Discovery","volume":"27","author":"Zauhar","year":"2013","journal-title":"J. Comput. Aided Mol. Des."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"33","DOI":"10.1186\/1758-2946-3-33","article-title":"Open Babel: An Open Chemical Toolbox","volume":"3","author":"Banck","year":"2011","journal-title":"J. Cheminformatics"},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Sousa da Silva, A.W., and Vranken, W.F. (2012). ACPYPE\u2014AnteChamber PYthon Parser interfacE. BMC Res. Notes, 5.","DOI":"10.1186\/1756-0500-5-367"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1157","DOI":"10.1002\/jcc.20035","article-title":"Development and Testing of a General Amber Force Field","volume":"25","author":"Wang","year":"2004","journal-title":"J. Comput. Chem."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1950","DOI":"10.1002\/prot.22711","article-title":"Improved Side-Chain Torsion Potentials for the Amber ff99SB Protein Force Field","volume":"78","author":"Piana","year":"2010","journal-title":"Proteins"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"926","DOI":"10.1063\/1.445869","article-title":"Comparison of Simple Potential Functions for Simulating Liquid Water","volume":"79","author":"Jorgensen","year":"1983","journal-title":"J. Chem. Phys."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"7182","DOI":"10.1063\/1.328693","article-title":"Polymorphic Transitions in Single Crystals: A New Molecular Dynamics Method","volume":"52","author":"Parrinello","year":"1981","journal-title":"J. Appl. Phys."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"014101","DOI":"10.1063\/1.2408420","article-title":"Canonical Sampling through Velocity Rescaling","volume":"126","author":"Bussi","year":"2007","journal-title":"J. Chem. Phys."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"1463","DOI":"10.1002\/(SICI)1096-987X(199709)18:12<1463::AID-JCC4>3.0.CO;2-H","article-title":"LINCS: A Linear Constraint Solver for Molecular Simulations","volume":"18","author":"Hess","year":"1997","journal-title":"J. Comput. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"10089","DOI":"10.1063\/1.464397","article-title":"Particle Mesh Ewald: An N\u22c5log(N) Method for Ewald Sums in Large Systems","volume":"98","author":"Darden","year":"1993","journal-title":"J. Chem. Phys."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"108895","DOI":"10.1016\/j.exer.2021.108895","article-title":"Cathepsin S Is a Novel Target for Age-Related Dry Eye","volume":"214","author":"Yu","year":"2022","journal-title":"Exp. Eye Res."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Gao, H., Zhang, Z., Deng, J., and Song, Y. (2025). Cathepsin S: Molecular Mechanisms in Inflammatory and Immunological Processes. Front. Immunol., 16.","DOI":"10.3389\/fimmu.2025.1600206"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Klinngam, W., Fu, R., Janga, S.R., Edman, M.C., and Hamm-Alvarez, S.F. (2018). Cathepsin S Alters the Expression of Pro-Inflammatory Cytokines and MMP-9, Partially through Protease\u2014Activated Receptor-2, in Human Corneal Epithelial Cells. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113530"},{"key":"ref_57","unstructured":"Keck School of Medicine Media Relations (2026, May 06). Finding the Role of Cathepsins in Corneal Neuropathic Pain. Newsroom. Available online: https:\/\/keck.usc.edu\/news\/finding-the-role-of-cathepsins-in-corneal-neuropathic-pain\/."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"jcs216317","DOI":"10.1242\/jcs.216317","article-title":"Cell Injury Triggers Actin Polymerization to Initiate Epithelial Restitution","volume":"131","author":"Aihara","year":"2018","journal-title":"J. Cell Sci."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"234","DOI":"10.1016\/j.jtos.2022.10.001","article-title":"Imbalanced IL-37\/TNF-\u03b1\/CTSS Signaling Disrupts Corneal Epithelial Barrier in a Dry Eye Model in Vitro","volume":"26","author":"Zhang","year":"2022","journal-title":"Ocul. Surf."},{"key":"ref_60","doi-asserted-by":"crossref","unstructured":"Kar, P., \u0110uki\u0107, N., Ahel, D., and Ahel, I. (Genes Dev., 2026). Structure, Function, Regulation, Evolution, and Therapeutic Implications of PARP14, Genes Dev., Online ahead of print.","DOI":"10.1101\/gad.353495.125"},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"101306","DOI":"10.1016\/j.preteyeres.2024.101306","article-title":"Eye on the Horizon: The Metabolic Landscape of the RPE in Aging and Disease","volume":"104","author":"Hansman","year":"2025","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/s41420-024-02159-0","article-title":"Multifaceted Mitochondrial as a Novel Therapeutic Target in Dry Eye: Insights and Interventions","volume":"10","author":"Ouyang","year":"2024","journal-title":"Cell Death Discov."},{"key":"ref_63","doi-asserted-by":"crossref","unstructured":"Fern\u00e1ndez-Ferreiro, A., and Gir\u00e1ldez-Fern\u00e1ndez, M.J. (2025). Special Issue \u201cMolecular Advances in Dry Eye Syndrome.\u201d. Int. J. Mol. Sci., 26.","DOI":"10.3390\/ijms262411863"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.mvr.2018.03.015","article-title":"Microvascular Abnormalities in Dry Eye Patients","volume":"118","author":"Chen","year":"2018","journal-title":"Microvasc. Res."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"193","DOI":"10.1016\/j.jtos.2016.12.002","article-title":"Bulbar Conjunctival Microvascular Responses in Dry Eye","volume":"15","author":"Chen","year":"2017","journal-title":"Ocul. Surf."},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"589","DOI":"10.4103\/tjo.TJO-D-25-00108","article-title":"Conjunctival Microvascular Alterations in Dry Eye Disease: A Comparative Study of Sj\u00f6gren\u2019s and Non-Sj\u00f6gren\u2019s Subtypes","volume":"15","author":"Lee","year":"2025","journal-title":"Taiwan J. Ophthalmol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"e2511957122","DOI":"10.1073\/pnas.2511957122","article-title":"Threonine Phosphorylation of STAT1 Safeguards Gut Epithelial Integrity and Restricts Interferon-Mediated Cytotoxicity","volume":"122","author":"Metwally","year":"2025","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_68","unstructured":"Moreno, I.Y. (2024). The Role of Hyaluronan in the Ocular Surface. [Ph.D. Thesis, University of Houston]."},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"551503","DOI":"10.2147\/OPTH.S551503","article-title":"Management of Dry Eye Disease with Artificial Tears Containing Hyaluronic Acid and Trehalose: A Narrative Review","volume":"20","author":"Barnett","year":"2026","journal-title":"Clin. Ophthalmol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"5491626","DOI":"10.1155\/2019\/5491626","article-title":"Oral Hyaluronic Acid Supplementation for the Treatment of Dry Eye Disease: A Pilot Study","volume":"2019","author":"Kim","year":"2019","journal-title":"J. Ophthalmol."},{"key":"ref_71","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1136\/bjo.2003.027573","article-title":"Sodium Hyaluronate (Hyaluronic Acid) Promotes Migration of Human Corneal Epithelial Cells in Vitro","volume":"88","author":"Gomes","year":"2004","journal-title":"Br. J. Ophthalmol."},{"key":"ref_72","doi-asserted-by":"crossref","first-page":"3713","DOI":"10.1167\/iovs.18-24292","article-title":"Hyaluronan Regulates Eyelid and Meibomian Gland Morphogenesis","volume":"59","author":"Sun","year":"2018","journal-title":"Investig. Ophthalmol. Vis. Sci."}],"container-title":["Current Issues in Molecular Biology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/5\/492\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,5,15]],"date-time":"2026-05-15T11:22:19Z","timestamp":1778844139000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1467-3045\/48\/5\/492"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,5,9]]},"references-count":72,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2026,5]]}},"alternative-id":["cimb48050492"],"URL":"https:\/\/doi.org\/10.3390\/cimb48050492","relation":{},"ISSN":["1467-3045"],"issn-type":[{"value":"1467-3045","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,5,9]]}}}