{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T06:16:01Z","timestamp":1788156961135,"version":"build-2803163510"},"reference-count":56,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Dry eye disease (DED) and anxiety are prevalent disorders that often coexist, yet the molecular mechanisms underlying their comorbidity remain inadequately understood. This study sought to elucidate the convergent genes, pathways, and immune signatures that link DED and anxiety by employing integrated bioinformatics and experimental validation approaches.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>Datasets (GSE44101, GSE98793) were retrieved from the GEO database. Weighted gene co-expression network analysis (WGCNA), differential expression analysis, and LASSO regression were utilized to identify candidate genes associated with comorbidity. Subsequently, functional enrichment analysis, protein\u2013protein interaction network analysis, immune infiltration deconvolution, and single-cell RNA sequencing were conducted. A comorbid DED-anxiety mouse model was developed using a combination of desiccating stress, 0.2% benzalkonium chloride, and chronic unpredictable mild stress. The expression of hub genes was validated through reverse transcription quantitative polymerase chain reaction(RT-qPCR) and Western blotting.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Researchers identified 128 candidate genes enriched in pathways like circadian rhythm. Four key genes (\n                      <jats:italic>BTBD1<\/jats:italic>\n                      ,\n                      <jats:italic>BANK1<\/jats:italic>\n                      ,\n                      <jats:italic>UBA3<\/jats:italic>\n                      ,\n                      <jats:italic>NEDD1<\/jats:italic>\n                      ) were highlighted for their expression in corneal epithelium cells. Immune analysis linked these genes to plasma cells and B cell subsets. In a mouse model, symptoms of dry eye, anxiety, inflammation, and neurotransmitter imbalance were observed, with the hub genes upregulated. RT-qPCR and Western blot analyses confirmed significant upregulation of\n                      <jats:italic>BTBD1<\/jats:italic>\n                      ,\n                      <jats:italic>BANK1<\/jats:italic>\n                      ,\n                      <jats:italic>UBA3<\/jats:italic>\n                      , and\n                      <jats:italic>NEDD1<\/jats:italic>\n                      in corneal tissues, while in the lacrimal gland and hippocampus,\n                      <jats:italic>BANK1<\/jats:italic>\n                      was elevated but\n                      <jats:italic>BTBD1<\/jats:italic>\n                      ,\n                      <jats:italic>UBA3<\/jats:italic>\n                      , and\n                      <jats:italic>NEDD1<\/jats:italic>\n                      were downregulated, indicating tissue-specific regulatory patterns.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      The study suggests\n                      <jats:italic>BTBD1<\/jats:italic>\n                      ,\n                      <jats:italic>BANK1<\/jats:italic>\n                      ,\n                      <jats:italic>UBA3<\/jats:italic>\n                      , and\n                      <jats:italic>NEDD1<\/jats:italic>\n                      are linked to immune-inflammatory features in DED-anxiety comorbidity, with distinct tissue-specific expression profiles observed across the cornea, lacrimal gland, and hippocampus, offering a basis for future research into shared pathways.\n                    <\/jats:p>\n                  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