Identification of glutamine as a potential therapeutic target in dry eye disease
Abstract Dry eye disease (DED) is a prevalent inflammatory condition significantly impacting quality of life, yet lacks effective pharmacological therapies. Herein, we proposed a novel approach to modulate the inflammation through metabolic remodeling, thus promoting dry eye recovery. Our study demo...
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| Format: | Article |
| Language: | English |
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Nature Publishing Group
2025-01-01
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| Series: | Signal Transduction and Targeted Therapy |
| Online Access: | https://doi.org/10.1038/s41392-024-02119-1 |
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| author | Xiaoniao Chen Chuyue Zhang Fei Peng Lingling Wu Deyi Zhuo Liqiang Wang Min Zhang Zhaohui Li Lei Tian Ying Jie Yifei Huang Xinji Yang Xiaoqi Li Fengyang Lei Yu Cheng |
| author_facet | Xiaoniao Chen Chuyue Zhang Fei Peng Lingling Wu Deyi Zhuo Liqiang Wang Min Zhang Zhaohui Li Lei Tian Ying Jie Yifei Huang Xinji Yang Xiaoqi Li Fengyang Lei Yu Cheng |
| author_sort | Xiaoniao Chen |
| collection | DOAJ |
| description | Abstract Dry eye disease (DED) is a prevalent inflammatory condition significantly impacting quality of life, yet lacks effective pharmacological therapies. Herein, we proposed a novel approach to modulate the inflammation through metabolic remodeling, thus promoting dry eye recovery. Our study demonstrated that co-treatment with mesenchymal stem cells (MSCs) and thymosin beta-4 (Tβ4) yielded the best therapeutic outcome against dry eye, surpassing monotherapy outcomes. In situ metabolomics through matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) revealed increased glutamine levels in cornea following MSC + Tβ4 combined therapy. Inhibition of glutamine reversed the anti-inflammatory, anti-apoptotic, and homeostasis-preserving effects observed with combined therapy, highlighting the critical role of glutamine in dry eye therapy. Clinical cases and rodent model showed elevated expression of glutaminase (GLS1), an upstream enzyme in glutamine metabolism, following dry eye injury. Mechanistic studies indicated that overexpression and inhibition of GLS1 counteracted and enhanced, respectively, the anti-inflammatory effects of combined therapy, underscoring GLS1’s pivotal role in regulating glutamine metabolism. Furthermore, single-cell sequencing revealed a distinct subset of pro-inflammatory and pro-fibrotic corneal epithelial cells in the dry eye model, while glutamine treatment downregulated those subclusters, thereby reducing their inflammatory cytokine secretion. In summary, glutamine effectively ameliorated inflammation and the occurrence of apoptosis by downregulating the pro-inflammatory and pro-fibrotic corneal epithelial cells subclusters and the related IκBα/NF-κB signaling. The present study suggests that glutamine metabolism plays a critical, previously unrecognized role in DED and proposes an attractive strategy to enhance glutamine metabolism by inhibiting the enzyme GLS1 and thus alleviating inflammation-driven DED progression. |
| format | Article |
| id | doaj-art-ac8ada3d50f7407eb8cb1c213954dec0 |
| institution | Kabale University |
| issn | 2059-3635 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Signal Transduction and Targeted Therapy |
| spelling | doaj-art-ac8ada3d50f7407eb8cb1c213954dec02025-01-26T12:54:27ZengNature Publishing GroupSignal Transduction and Targeted Therapy2059-36352025-01-0110111810.1038/s41392-024-02119-1Identification of glutamine as a potential therapeutic target in dry eye diseaseXiaoniao Chen0Chuyue Zhang1Fei Peng2Lingling Wu3Deyi Zhuo4Liqiang Wang5Min Zhang6Zhaohui Li7Lei Tian8Ying Jie9Yifei Huang10Xinji Yang11Xiaoqi Li12Fengyang Lei13Yu Cheng14Department of Ophthalmology, the Third Medical Center of Chinese PLA General HospitalDepartment of Nephrology, the First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney DiseasesDepartment of Nephrology, the First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney DiseasesDepartment of Nephrology, the First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney DiseasesDepartment of Ophthalmology, the Third Medical Center of Chinese PLA General HospitalDepartment of Ophthalmology, the Third Medical Center of Chinese PLA General HospitalDepartment of Nephrology, the First Medical Center of Chinese PLA General Hospital, State Key Laboratory of Kidney DiseasesDepartment of Ophthalmology, the Third Medical Center of Chinese PLA General HospitalBeijing Institute of Ophthalmology, Beijing TongRen Eye Center, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical UniversityBeijing Institute of Ophthalmology, Beijing TongRen Eye Center, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical UniversityDepartment of Ophthalmology, the Third Medical Center of Chinese PLA General HospitalDepartment of Ophthalmology, the Third Medical Center of Chinese PLA General HospitalDepartment of Ophthalmology, the Third Medical Center of Chinese PLA General HospitalBeijing Institute of Ophthalmology, Beijing TongRen Eye Center, Beijing Key Laboratory of Ophthalmology and Visual Sciences, Beijing Tongren Hospital, Capital Medical UniversityDepartment of Ophthalmology, the Third Medical Center of Chinese PLA General HospitalAbstract Dry eye disease (DED) is a prevalent inflammatory condition significantly impacting quality of life, yet lacks effective pharmacological therapies. Herein, we proposed a novel approach to modulate the inflammation through metabolic remodeling, thus promoting dry eye recovery. Our study demonstrated that co-treatment with mesenchymal stem cells (MSCs) and thymosin beta-4 (Tβ4) yielded the best therapeutic outcome against dry eye, surpassing monotherapy outcomes. In situ metabolomics through matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) revealed increased glutamine levels in cornea following MSC + Tβ4 combined therapy. Inhibition of glutamine reversed the anti-inflammatory, anti-apoptotic, and homeostasis-preserving effects observed with combined therapy, highlighting the critical role of glutamine in dry eye therapy. Clinical cases and rodent model showed elevated expression of glutaminase (GLS1), an upstream enzyme in glutamine metabolism, following dry eye injury. Mechanistic studies indicated that overexpression and inhibition of GLS1 counteracted and enhanced, respectively, the anti-inflammatory effects of combined therapy, underscoring GLS1’s pivotal role in regulating glutamine metabolism. Furthermore, single-cell sequencing revealed a distinct subset of pro-inflammatory and pro-fibrotic corneal epithelial cells in the dry eye model, while glutamine treatment downregulated those subclusters, thereby reducing their inflammatory cytokine secretion. In summary, glutamine effectively ameliorated inflammation and the occurrence of apoptosis by downregulating the pro-inflammatory and pro-fibrotic corneal epithelial cells subclusters and the related IκBα/NF-κB signaling. The present study suggests that glutamine metabolism plays a critical, previously unrecognized role in DED and proposes an attractive strategy to enhance glutamine metabolism by inhibiting the enzyme GLS1 and thus alleviating inflammation-driven DED progression.https://doi.org/10.1038/s41392-024-02119-1 |
| spellingShingle | Xiaoniao Chen Chuyue Zhang Fei Peng Lingling Wu Deyi Zhuo Liqiang Wang Min Zhang Zhaohui Li Lei Tian Ying Jie Yifei Huang Xinji Yang Xiaoqi Li Fengyang Lei Yu Cheng Identification of glutamine as a potential therapeutic target in dry eye disease Signal Transduction and Targeted Therapy |
| title | Identification of glutamine as a potential therapeutic target in dry eye disease |
| title_full | Identification of glutamine as a potential therapeutic target in dry eye disease |
| title_fullStr | Identification of glutamine as a potential therapeutic target in dry eye disease |
| title_full_unstemmed | Identification of glutamine as a potential therapeutic target in dry eye disease |
| title_short | Identification of glutamine as a potential therapeutic target in dry eye disease |
| title_sort | identification of glutamine as a potential therapeutic target in dry eye disease |
| url | https://doi.org/10.1038/s41392-024-02119-1 |
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