{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:59:07Z","timestamp":1790657947268,"version":"4.1.0"},"reference-count":57,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T00:00:00Z","timestamp":1790640000000},"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>Introduction<\/jats:title>\n                    <jats:p>Non-infectious uveitis associated with systemic diseases is a sight-threatening inflammatory disorder often associated with dysregulated immune responses and oxidative stress. Although redox imbalance is thought to contribute to its pathogenesis, the precise molecular mechanisms remain poorly defined.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>We performed transcriptomic analysis of human non-infectious uveitis datasets (GSE17114 and GSE18781) encompassing Beh\u00e7et's uveitis (BU), sarcoidosis-associated uveitis, and spondyloarthropathy (SpA)-associated uveitis, combined with experimental validation to elucidate oxidative stress-associated mechanisms.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>We identified 1,821 differentially expressed genes (DEGs) enriched in immune cell migration, T and B cell signaling, and T cell activation pathways. Among the oxidative stress-associated DEGs, six genes were validated in patients with BU: SPHK1, MMP8, and ARG1 were upregulated, while CCR7, PDGFD, and DDIT4 were downregulated. Knockdown of SPHK1 reduced ROS production, lipid peroxidation, and NLRP3 inflammasome-mediated pyroptosis, decreasing IL-1\u03b2 and IL-18 secretion; SPHK1 overexpression promoted pyroptosis, reversed by the ROS inhibitor N-acetylcysteine. Molecular docking revealed strong binding affinity between SPHK1 and dexamethasone. All six oxidative stress-related DEGs demonstrated strong diagnostic potential. Immune cell abundance profiling revealed a significant decrease in activated CD4+ T cells, memory B cells, and NK cells in peripheral blood.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Discussion<\/jats:title>\n                    <jats:p>Collectively, our findings highlight SPHK1 as a key mediator of oxidative stress-induced pyroptosis in non-infectious uveitis and propose the SPHK1\u2013ROS\u2013pyroptosis axis as a potential therapeutic target.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2026.1764448","type":"journal-article","created":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T04:39:57Z","timestamp":1790656797000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["SPHK1 drives pyroptosis via ROS-dependent activation of the NLRP3 inflammasome in non-infectious 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