cGAS - novel therapeutic target for uveitis
en-GBde-DEes-ESfr-FR

cGAS - novel therapeutic target for uveitis

16/04/2026 Compuscript Ltd
The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway—a key cytosolic DNA sensor and crucial mediator of inflammation related to infection and cellular stress—has been implicated in the pathogenesis of several ocular diseases, including diabetic retinopathy, age-related macular degeneration, and uveal melanoma.

In a recent study published in Genes & Diseases, researchers from Fudan University, Key Laboratory of Myopia of State Health Ministry, and Peking University People’s Hospital investigated the role of this pathway in mediating inflammatory responses within the EIU model.

Using intravitreal lipopolysaccharide (LPS) injections to induce acute ocular inflammation, the authors first characterized the activation of the cGAS–STING signaling cascade in retinal tissue. Molecular analyses demonstrated that the LPS challenge was associated with the enhanced activation of downstream effectors, including TBK1 and IRF3. Concomitantly, increased levels of cytosolic mitochondrial DNA (mtDNA) were observed, suggesting that mitochondrial stress provides the endogenous ligands necessary to amplify inflammatory signaling during endotoxin exposure. Transcriptomic profiling further revealed an enrichment of DNA-sensing and innate immune response pathways, supporting a functional role for cGAS in the inflammatory milieu.

To evaluate the specific contribution of cGAS, the investigators employed cGAS knockout (cGAS⁻/⁻) mice. Genetic ablation of cGAS markedly attenuated the clinical and histopathological manifestations of uveitis. Compared with wild-type controls, cGAS-deficient mice exhibited reduced vitreous haze, diminished retinal vascular leakage, and decreased inflammatory cell infiltration. Furthermore, leukocyte adhesion and macrophage recruitment were significantly reduced, and microglial activation—a key driver of retinal inflammatory amplification—was substantially suppressed. These phenotypic changes correlated with a significant downregulation of NF-κB and MAPK signaling, preserved blood–retinal barrier integrity, and an inhibition of the large-scale upregulation of genes associated with innate immunity and interferon signaling.

Mechanistically, the study reveals that cGAS senses LPS-induced mtDNA release, catalyzing 2'3'-cGAMP production to activate STING and propagate inflammatory cascades. Inhibiting this axis disrupts the feed-forward loop of pyroptosis, inflammasome activation, and cytokine storms, resulting in reduced inflammation and improved structural preservation. These findings position cGAS inhibitors as promising adjuncts to corticosteroids, particularly for steroid-refractory uveitis.

In conclusion, by delineating the cGAS–STING–TBK1–IRF3 axis, this study identifies cGAS as a pivotal mediator of endotoxin-induced ocular inflammation and highlights it as a high-value therapeutic target for modulating intraocular inflammatory diseases.

Reference
Title of the original paper : cGAS knockout inhibited endotoxin-induced uveitis in mice

Journal : Genes & Diseases
Genes & Diseases is a journal for molecular and translational medicine. The journal primarily focuses on publishing investigations on the molecular bases and experimental
therapeutics of human diseases. Publication formats include full length research article, review article, short communication, correspondence, perspectives, commentary, views on news, and research watch.

DOI : https://doi.org/10.1016/j.gendis.2025.101786

Funding Information:
  • National Key R&D Program of China (No. 2022YFC2404203)
  • National Natural Science Foundation of China (No. 82070980)
  • Shanghai Hospital Development Center Foundation (China) (No. SHDC12023116)
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Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.

Scopus CiteScore: 8.4
Impact Factor: 9.4

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More information: https://www.keaipublishing.com/en/journals/genes-and-diseases/
Editorial Board: https://www.keaipublishing.com/en/journals/genes-and-diseases/editorial-board/
All issues and articles in press are available online in ScienceDirect (https://www.sciencedirect.com/journal/genes-and-diseases).
Submissions to Genes & Diseases may be made using Editorial Manager (https://www.editorialmanager.com/gendis/default.aspx).

Print ISSN: 2352-4820
eISSN: 2352-3042
CN: 50-1221/R

Contact Us: editor@genesndiseases.cn
X (formerly twitter): @GenesNDiseases (https://x.com/GenesNDiseases)

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https://tinyurl.com/musznsh8
Attached files
  • GO enrichment analysis and KEGG pathway analysis of co-expressed mRNA targets in the NC and EIU groups (A–C) GO enrichment analysis of co-expressed mRNA targets, covering biological processes, cellular components, and molecular functions. The top 10 GO terms of each domain are shown. (D) The top 10 enriched KEGG terms. (E) Real-time PCR was used to quantify the number of miDNA copies in the cytoplasm. The released mtDNA was significantly increased at 24 h and 48 h in the EIU groups. ∗∗P < 0.01. n = 3 biological replicates in each group. (F) GSEA snapshots of cytosolic DNA-sensing pathway enrichment analysis. (G) Hierarchical clustering heatmap analysis of cytosolic DNA-sensing pathway mRNAs. (H) The cGAS-STING-TF-inflammatory network. NC, normal control; EIU, endotoxin-induced uveitis; GSEA, gene set enrichment analysis; GO, gene ontology; KEGG, Kyoto Encyclopedia of Genes and Genomes; cGAS, cyclic guanosine monophosphate-adenosine monophosphate synthase; STING, stimulator of interferon genes; TF, transcription factor.
  • Representative fundus photographs (A–D) and FFA (E–H) of the retinas in the NC and EIU groups : (A) Fundus photograph from the WT NC group. (B) Fundus photograph from the KO NC group. (C) Fundus photograph from the WT EIU group. (D) Fundus photograph from the KO EIU group. (E) FFA from the WT NC group. (F) FFA from the KO NC group. (G) FFA from the WT EIU group. (H) FFA from the KO EIU group. (I) Grade of the severity of vitreous opacity. ∗∗P < 0.01. n = 3 biological replicates per group. FFA, fundus fluorescein angiography; WT, wild type; KO, Cgas knockout; NC, normal control; EIU, endotoxin-induced uveitis
  • Analysis and confirmation of the differentially expressed mRNAs in the KO and WT EIU groups (A) Principal component analysis of retinal mRNA expression levels in the KO EIU and WT EIU groups. The distribution of dots indicates distinct mRNA expression patterns between KO EIU and WT EIU. (B) Volcano plot of total mRNAs. The red, blue, and gray dots represent up-regulated, down-regulated, and non-significantly altered mRNAs, respectively. The data at infinity are not shown. (C) Hierarchical clustering heatmap analysis of differentially expressed mRNAs. The red represents increased expression, and the blue represents decreased expression. (D–F) GO enrichment analysis of co-expressed mRNA targets, covering biological processes, cellular components, and molecular functions. The top 10 GO terms of each domain are shown. WT, wild type; KO, Cgas knockout; NC, normal control; EIU, endotoxin-induced uveitis; GO, gene ontology
16/04/2026 Compuscript Ltd
Regions: Europe, Ireland, United Kingdom, Asia, China
Keywords: Science, Life Sciences

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