Experimental eye research · 2026
Clioquinol alleviates Aspergillus fumigatus keratitis through antifungal and anti-inflammatory effects associated with metal chelation and Nrf2/HO-1 signaling.
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Wei Zhipeng, Yu Bing, Lin Jing, Wang Qian, Zhang Lina, Chi Menghui, Wang Ziyi, Li Yuqi, Sun Yuxuan, Li Cui, Zhao Guiqiu
Аннотация
PURPOSE: To investigate the therapeutic efficacy of Clioquinol (CLIO) against Aspergillus fumigatus (A. fumigatus) keratitis and its underlying mechanisms.
METHODS: The antifungal activity of CLIO was evaluated by minimum inhibitory concentration (MIC) assays, metal ion rescue assays, biofilm disruption assays, Calcofluor white staining, propidium iodide staining, and scanning electron microscopy. Fungal genes related to metal ion uptake and homeostasis were measured by RT-qPCR. CCK-8 assay, adhesion assay, and Draize eye test were used to assess the biological safety of CLIO. Immunofluorescence and HE staining were used to detect inflammatory cell infiltration. RT-qPCR, ELISA, and Western blot were applied to assess cytokines, pattern recognition receptors, and Nrf2/HO-1 expression.
RESULTS: CLIO inhibited A. fumigatus spore germination and growth, disrupted mature biofilms, and altered hyphal morphology. Exogenous Fe3+ supplementation attenuated its antifungal activity, and CLIO increased the expression of fungal genes related to metal ion uptake. CLIO markedly suppressed the A. fumigatus-induced inflammatory response in RAW264.7 cells, reducing IL-1β, IL-6, and TNF-α expression. Meanwhile, CLIO increased Nrf2 expression and promoted its nuclear translocation, accompanied by increased HO-1 expression. The inhibition of Nrf2 partially reversed the inhibitory effects of CLIO on inflammatory cytokine expression. In vivo, CLIO significantly alleviated A. fumigatus keratitis in mice, reduced corneal inflammation, and decreased fungal burden.
CONCLUSION: CLIO showed therapeutic potential in experimental fungal keratitis through combined antifungal and anti-inflammatory effects. Its antifungal activity may involve metal ion chelation and disruption of fungal metal homeostasis, while its anti-inflammatory effect may be associated with the Nrf2/HO-1 pathway.
METHODS: The antifungal activity of CLIO was evaluated by minimum inhibitory concentration (MIC) assays, metal ion rescue assays, biofilm disruption assays, Calcofluor white staining, propidium iodide staining, and scanning electron microscopy. Fungal genes related to metal ion uptake and homeostasis were measured by RT-qPCR. CCK-8 assay, adhesion assay, and Draize eye test were used to assess the biological safety of CLIO. Immunofluorescence and HE staining were used to detect inflammatory cell infiltration. RT-qPCR, ELISA, and Western blot were applied to assess cytokines, pattern recognition receptors, and Nrf2/HO-1 expression.
RESULTS: CLIO inhibited A. fumigatus spore germination and growth, disrupted mature biofilms, and altered hyphal morphology. Exogenous Fe3+ supplementation attenuated its antifungal activity, and CLIO increased the expression of fungal genes related to metal ion uptake. CLIO markedly suppressed the A. fumigatus-induced inflammatory response in RAW264.7 cells, reducing IL-1β, IL-6, and TNF-α expression. Meanwhile, CLIO increased Nrf2 expression and promoted its nuclear translocation, accompanied by increased HO-1 expression. The inhibition of Nrf2 partially reversed the inhibitory effects of CLIO on inflammatory cytokine expression. In vivo, CLIO significantly alleviated A. fumigatus keratitis in mice, reduced corneal inflammation, and decreased fungal burden.
CONCLUSION: CLIO showed therapeutic potential in experimental fungal keratitis through combined antifungal and anti-inflammatory effects. Its antifungal activity may involve metal ion chelation and disruption of fungal metal homeostasis, while its anti-inflammatory effect may be associated with the Nrf2/HO-1 pathway.