Investigative ophthalmology & visual science · 2026
Ly93 Inhibits Sphingomyelin Synthesis and Attenuates Inflammation and Injury in Dry Eye Conjunctival Organoids.
СтатьяПоддержка исследования: вне правительства СШАНазвание и аннотация: Перевод в очереди
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Chen Qiankun, Wei Yuan, Wang Leying, Liang Junqi, Pang Jinding, Han Yiping, Qudsi Ahyan Ilman, Liang Qingfeng
Аннотация
PURPOSE: We aimed to investigate the pathogenic role of sphingomyelin (SM) in dry eye disease (DED) and evaluate Ly93, an SM synthase inhibitor, as a potential therapy for DED-associated inflammation.
METHODS: Tear samples from DED patients and healthy participants were analyzed for SM concentrations using liquid chromatography-tandem mass spectrometry. Correlations between SM levels and clinical parameters were evaluated. The effects of SM on normal conjunctival organoids and the therapeutic efficacy of Ly93 on hyperosmolarity-induced DED conjunctival organoids were investigated. SM levels after treatment with Ly93 were also measured. The inflammatory cytokines (IL-1β, IL-6, and MMP-9), signaling pathways (STAT1, nuclear factor-κB, and PI3K), apoptosis (caspase-3 and caspase-9), ferroptosis (Fe2+, GPX4, TFR, and 4-HNE) were analyzed.
RESULTS: Tear SM concentrations were significantly elevated in DED patients and positively correlated with disease severity. Exogenous SM upregulated STAT1, IL-1β, IL-6, and inducible nitric oxide synthase expression in conjunctival organoids. Hyperosmolarity-induced DED conjunctival organoids exhibited elevated MMP-9 and IL-1β, activated signaling pathways (nuclear factor-κB, STAT1, and PI3K), increased apoptosis (caspase-3 and caspase-9), and ferroptosis (elevated Fe2+, TFR, and 4-HNE, and decreased GPX4). Ly93 treatment effectively reduced SM levels and attenuated inflammation, apoptosis, and ferroptosis in the DED organoid model.
CONCLUSIONS: Our study demonstrates that elevated SM promotes ocular surface inflammation and cellular injury. Inhibition of SM synthase by Ly93 alleviates DED-associated inflammation and injury, suggesting that targeting SM metabolism represents a promising therapeutic strategy.
METHODS: Tear samples from DED patients and healthy participants were analyzed for SM concentrations using liquid chromatography-tandem mass spectrometry. Correlations between SM levels and clinical parameters were evaluated. The effects of SM on normal conjunctival organoids and the therapeutic efficacy of Ly93 on hyperosmolarity-induced DED conjunctival organoids were investigated. SM levels after treatment with Ly93 were also measured. The inflammatory cytokines (IL-1β, IL-6, and MMP-9), signaling pathways (STAT1, nuclear factor-κB, and PI3K), apoptosis (caspase-3 and caspase-9), ferroptosis (Fe2+, GPX4, TFR, and 4-HNE) were analyzed.
RESULTS: Tear SM concentrations were significantly elevated in DED patients and positively correlated with disease severity. Exogenous SM upregulated STAT1, IL-1β, IL-6, and inducible nitric oxide synthase expression in conjunctival organoids. Hyperosmolarity-induced DED conjunctival organoids exhibited elevated MMP-9 and IL-1β, activated signaling pathways (nuclear factor-κB, STAT1, and PI3K), increased apoptosis (caspase-3 and caspase-9), and ferroptosis (elevated Fe2+, TFR, and 4-HNE, and decreased GPX4). Ly93 treatment effectively reduced SM levels and attenuated inflammation, apoptosis, and ferroptosis in the DED organoid model.
CONCLUSIONS: Our study demonstrates that elevated SM promotes ocular surface inflammation and cellular injury. Inhibition of SM synthase by Ly93 alleviates DED-associated inflammation and injury, suggesting that targeting SM metabolism represents a promising therapeutic strategy.