{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T06:28:06Z","timestamp":1786429686189,"version":"build-2736575974"},"reference-count":76,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T00:00:00Z","timestamp":1786406400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Bisphenol A (BPA) is a pervasive environmental contaminant associated with various systemic toxicities. However, its specific mechanistic involvement in dry eye disease (DED) pathogenesis is not defined. This study aimed to evaluate the toxicological mechanisms of BPA in DED pathogenesis and identify the key molecular mediators driving ocular surface injury.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Toxicity profiles of BPA were predicted using the ProTox and ADMETlab platforms. Network toxicology and machine learning were used to explore pathogenic pathways and molecular mechanisms. Mendelian randomization (MR) analysis was performed to assess the causal effects of candidate targets on DED. Immune infiltration analysis and Gene Set Enrichment Analysis (GSEA) were used to characterize functional features and immune associations. Molecular docking and molecular dynamics (MD) simulations evaluated the spatial engagement and stability between BPA and the hub target. Finally,\n                      <jats:italic>in vitro<\/jats:italic>\n                      assays (CCK-8, LDH release, propidium iodide staining, ROS detection, qRT-PCR, and Western blot) using human corneal epithelial cells (HCECs) were conducted to validate the BPA-induced cytotoxicity and the molecular mechanisms.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Toxicity assessments predicted significant ocular irritant and corrosive properties for BPA. Machine learning algorithms identified\n                      <jats:italic>CASP1<\/jats:italic>\n                      as the hub gene. MR analysis provided genetic evidence that elevated\n                      <jats:italic>CASP1<\/jats:italic>\n                      expression causally increases DED risk (OR = 1.11, 95% CI: 1.06\u20131.16). Molecular docking demonstrated stable binding affinity (\u22125.1\u00a0kcal\/mol) between BPA and the CASP1 protein. 100-ns molecular dynamics simulations confirmed its structural equilibrium and spontaneous thermodynamic stability with an MM-PBSA binding free energy of \u221212.19\u00a0kcal\/mol.\n                      <jats:italic>In vitro<\/jats:italic>\n                      , BPA exposure decreased HCEC viability, compromised membrane integrity, and triggered significant intracellular ROS accumulation. BPA significantly upregulated the mRNA and protein expression of\n                      <jats:italic>caspase-1<\/jats:italic>\n                      ,\n                      <jats:italic>GSDMD<\/jats:italic>\n                      ,\n                      <jats:italic>IL-1\u03b2<\/jats:italic>\n                      , and\n                      <jats:italic>IL-18<\/jats:italic>\n                      . The application of a\n                      <jats:italic>CASP1<\/jats:italic>\n                      inhibitor reversed these alterations and mitigated ROS accumulation.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>\n                      This study suggests that\n                      <jats:italic>CASP1<\/jats:italic>\n                      is a central molecular component in DED. BPA promotes ocular surface injury by activating the\n                      <jats:italic>CASP1<\/jats:italic>\n                      \/\n                      <jats:italic>GSDMD<\/jats:italic>\n                      -mediated pyroptotic axis and its associated inflammatory cascade. Inhibition of\n                      <jats:italic>CASP1<\/jats:italic>\n                      effectively abrogates this process, suggesting potential avenues for clinical intervention.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fphar.2026.1880522","type":"journal-article","created":{"date-parts":[[2026,8,11]],"date-time":"2026-08-11T05:37:26Z","timestamp":1786426646000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Bisphenol A exacerbates dry eye disease via the CASP1\/GSDMD-mediated pyroptotic axis: network toxicology, mendelian randomization, and experimental validation"],"prefix":"10.3389","volume":"17","author":[{"given":"Yingchen","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Ophthalmology, The Affiliated Hospital of Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenhong","family":"Jiang","sequence":"additional","affiliation":[{"name":"Qingdao Medical College, Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, No.971 Hospital of the People\u2019s Liberation Army Navy","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangrui","family":"Liu","sequence":"additional","affiliation":[{"name":"Qingdao Medical College, Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kang","family":"Lu","sequence":"additional","affiliation":[{"name":"Qingdao Medical College, Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youhai","family":"Wang","sequence":"additional","affiliation":[{"name":"Qingdao Medical College, Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Minglu","family":"Xu","sequence":"additional","affiliation":[{"name":"Qingdao Medical College, Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qing","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, The Affiliated Hospital of Qingdao University","place":["Qingdao, Shandong, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,8,11]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"1559325815610582","DOI":"10.1177\/1559325815610582","article-title":"Molecular mechanisms of action of BPA","volume":"13","author":"Acconcia","year":"2015","journal-title":"Dose-Response"},{"key":"B2","doi-asserted-by":"publisher","first-page":"108728","DOI":"10.1016\/j.envint.2024.108728","article-title":"Exploring BPA alternatives - environmental levels and toxicity review","volume":"189","author":"Adamovsky","year":"2024","journal-title":"Environ. 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