{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T05:46:56Z","timestamp":1775108816581,"version":"3.50.1"},"reference-count":20,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T00:00:00Z","timestamp":1774915200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Science and Technology","award":["2022YFF1202901"],"award-info":[{"award-number":["2022YFF1202901"]}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"crossref","award":["82171404"],"award-info":[{"award-number":["82171404"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background: Primary open-angle glaucoma (POAG) is a leading cause of irreversible blindness worldwide, characterized by progressive optic nerve degeneration and marked molecular heterogeneity. Increasing evidence indicates that metabolic dysregulation and immune remodeling contribute to POAG pathogenesis; however, the underlying regulatory networks and reliable diagnostic biomarkers remain incompletely defined. Methods: Bulk transcriptomic and single-cell RNA sequencing (scRNA-seq) datasets of trabecular meshwork tissues were retrieved from Gene Expression Omnibus (GEO). Differential expression analysis and weighted gene co-expression network analysis (WGCNA) were performed to identify disease-associated modules. A machine learning framework was applied to construct classification models. Estimated immune-cell fractions were assessed using CIBERSORT, followed by pathway and transcription factor analyses. Single-cell analysis was conducted to examine the cell type-specific expression patterns. Results: A total of 195 differentially expressed genes were identified between POAG and control samples. WGCNA revealed a lactylation-related module strongly correlated with disease status. Machine learning identified S100A2 and S100A14 as candidate diagnostic biomarkers with consistent classification performance across datasets. Immune infiltration analysis suggested alterations in the immune microenvironment in POAG. Single-cell data showed that the model genes exhibited sparse but non-uniform expression across cell populations. Conclusions: This integrative analysis prioritizes S100A2 and S100A14 as candidate diagnostic biomarkers for POAG and indicates potential associations with immune-metabolic regulatory mechanisms.<\/jats:p>","DOI":"10.3390\/genes17040403","type":"journal-article","created":{"date-parts":[[2026,3,31]],"date-time":"2026-03-31T16:34:08Z","timestamp":1774974848000},"page":"403","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Lactylation-Associated Immune Metabolic Reprogramming Identifies S100A2 and S100A14 as Candidate Diagnostic Biomarkers in Primary Open-Angle Glaucoma: An Integrated Bulk and Single-Cell Transcriptomic Analysis"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0009-0004-2949-4769","authenticated-orcid":false,"given":"Yu","family":"Xu","sequence":"first","affiliation":[{"name":"Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xin","family":"Fu","sequence":"additional","affiliation":[{"name":"Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yajun","family":"Gong","sequence":"additional","affiliation":[{"name":"Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fangyuan","family":"Zeng","sequence":"additional","affiliation":[{"name":"Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Min","family":"Tang","sequence":"additional","affiliation":[{"name":"Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sixian","family":"Hu","sequence":"additional","affiliation":[{"name":"Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Guangyi","family":"Huang","sequence":"additional","affiliation":[{"name":"Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tianxian","family":"Tu","sequence":"additional","affiliation":[{"name":"Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaolai","family":"Zhou","sequence":"additional","affiliation":[{"name":"Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou 510623, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,31]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"16067","DOI":"10.1038\/nrdp.2016.67","article-title":"Primary Open-Angle Glaucoma","volume":"2","author":"Weinreb","year":"2016","journal-title":"Nat. Rev. Dis. Primer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1901","DOI":"10.1001\/jama.2014.3192","article-title":"The Pathophysiology and Treatment of Glaucoma: A Review","volume":"311","author":"Weinreb","year":"2014","journal-title":"JAMA"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2081","DOI":"10.1016\/j.ophtha.2014.05.013","article-title":"Global Prevalence of Glaucoma and Projections of Glaucoma Burden through 2040: A Systematic Review and Meta-Analysis","volume":"121","author":"Tham","year":"2014","journal-title":"Ophthalmology"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1007\/BF00496153","article-title":"Electrn Microscopic Studies on the Trabecular Meshwork in Glaucoma Simplex","volume":"183","author":"Rohen","year":"1972","journal-title":"Albrecht von Graefes Arch. Klin. Ophthalmol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1016\/j.preteyeres.2006.07.003","article-title":"Oxidative Stress in Glaucomatous Neurodegeneration: Mechanisms and Consequences","volume":"25","author":"Tezel","year":"2006","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1016\/j.exer.2017.02.014","article-title":"Neuroinflammation in Glaucoma: A New Opportunity","volume":"157","author":"Williams","year":"2017","journal-title":"Exp. Eye Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1172\/JCI61135","article-title":"Radiation Treatment Inhibits Monocyte Entry into the Optic Nerve Head and Prevents Neuronal Damage in a Mouse Model of Glaucoma","volume":"122","author":"Howell","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1093\/hmg\/ddae003","article-title":"High Throughput Functional Profiling of Genes at Intraocular Pressure Loci Reveals Distinct Networks for Glaucoma","volume":"33","author":"Greatbatch","year":"2024","journal-title":"Hum. Mol. Genet."},{"key":"ref_9","first-page":"774","article-title":"Genome-Wide Expression Profile of Human Trabecular Meshwork Cultured Cells, Nonglaucomatous and Primary Open Angle Glaucoma Tissue","volume":"12","author":"Liton","year":"2006","journal-title":"Mol. Vis."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1888","DOI":"10.1016\/j.cell.2019.05.031","article-title":"Comprehensive Integration of Single-Cell Data","volume":"177","author":"Stuart","year":"2019","journal-title":"Cell"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"10339","DOI":"10.1073\/pnas.2001250117","article-title":"Cell Atlas of Aqueous Humor Outflow Pathways in Eyes of Humans and Four Model Species Provides Insight into Glaucoma Pathogenesis","volume":"117","author":"Yan","year":"2020","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1038\/s41586-019-1678-1","article-title":"Metabolic Regulation of Gene Expression by Histone Lactylation","volume":"574","author":"Zhang","year":"2019","journal-title":"Nature"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1038\/s41392-024-02082-x","article-title":"Lactate and Lactylation in Cancer","volume":"10","author":"Chen","year":"2025","journal-title":"Signal Transduct. Target. Ther."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1016\/j.ophtha.2018.01.023","article-title":"Efficacy of a Deep Learning System for Detecting Glaucomatous Optic Neuropathy Based on Color Fundus Photographs","volume":"125","author":"Li","year":"2018","journal-title":"Ophthalmology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.exer.2010.07.009","article-title":"The Immune Response in Glaucoma: A Perspective on the Roles of Oxidative Stress","volume":"93","author":"Tezel","year":"2011","journal-title":"Exp. Eye Res."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Langfelder, P., and Horvath, S. (2008). WGCNA: An R Package for Weighted Correlation Network Analysis. BMC Bioinform., 9.","DOI":"10.1186\/1471-2105-9-559"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"101695","DOI":"10.1016\/j.media.2020.101695","article-title":"Towards Multi-Center Glaucoma OCT Image Screening with Semi-Supervised Joint Structure and Function Multi-Task Learning","volume":"63","author":"Wang","year":"2020","journal-title":"Med. Image Anal."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"24","DOI":"10.2174\/156652413804486214","article-title":"Functions of S100 Proteins","volume":"13","author":"Donato","year":"2013","journal-title":"Curr. Mol. Med."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"152","DOI":"10.1016\/j.preteyeres.2011.11.002","article-title":"The Molecular Basis of Retinal Ganglion Cell Death in Glaucoma","volume":"31","author":"Almasieh","year":"2012","journal-title":"Prog. Retin. Eye Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"262","DOI":"10.1136\/bjo.2005.081224","article-title":"The Number of People with Glaucoma Worldwide in 2010 and 2020","volume":"90","author":"Quigley","year":"2006","journal-title":"Br. J. Ophthalmol."}],"container-title":["Genes"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/403\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T04:22:59Z","timestamp":1775103779000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4425\/17\/4\/403"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,3,31]]},"references-count":20,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2026,4]]}},"alternative-id":["genes17040403"],"URL":"https:\/\/doi.org\/10.3390\/genes17040403","relation":{},"ISSN":["2073-4425"],"issn-type":[{"value":"2073-4425","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,3,31]]}}}