Frontiers in immunology · 2026
SPHK1 drives pyroptosis via ROS-dependent activation of the NLRP3 inflammasome in non-infectious uveitis.
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Hu Lili, Pan Shaoxin, Wang Jing, Mei Suyin, Pan Haoning, Chang Rui
Аннотация
INTRODUCTION: 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.
METHODS: We performed transcriptomic analysis of human non-infectious uveitis datasets (GSE17114 and GSE18781) encompassing Behçet's uveitis (BU), sarcoidosis-associated uveitis, and spondyloarthropathy (SpA)-associated uveitis, combined with experimental validation to elucidate oxidative stress-associated mechanisms.
RESULTS: 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-1β 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.
DISCUSSION: Collectively, our findings highlight SPHK1 as a key mediator of oxidative stress-induced pyroptosis in non-infectious uveitis and propose the SPHK1-ROS-pyroptosis axis as a potential therapeutic target.
METHODS: We performed transcriptomic analysis of human non-infectious uveitis datasets (GSE17114 and GSE18781) encompassing Behçet's uveitis (BU), sarcoidosis-associated uveitis, and spondyloarthropathy (SpA)-associated uveitis, combined with experimental validation to elucidate oxidative stress-associated mechanisms.
RESULTS: 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-1β 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.
DISCUSSION: Collectively, our findings highlight SPHK1 as a key mediator of oxidative stress-induced pyroptosis in non-infectious uveitis and propose the SPHK1-ROS-pyroptosis axis as a potential therapeutic target.