ArticleJournal of neuroinflammation2023
The BET PROTAC inhibitor dBET6 protects against retinal degeneration and inhibits the cGAS-STING in response to light damage.
Article in Journal of neuroinflammation, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 22 papers.
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Who cites it
22 citing papers in PubMed, 36 citations in OpenAlex.
- The cGAS-STING pathway: mechanistic basis, dual biological functions and translational therapeutic advances.Apoptosis : an international journal on programmed cell death · 2026Review
- The Role of S100A8/A9 in Autoimmune Eye Diseases: From Pathogenesis to Targeted Therapy.Investigative ophthalmology & visual science · 2026Review
- Design of Synthesizable PROTACs through Synthesis Constrained Generative Model and Reinforcement Learning.JACS Au · 2026Article
- Eyes Toward the Clinic: Selective Inhibition and Degradation Approaches to Bromodomain-Containing Proteins.Chembiochem : a European journal of chemical biology · 2026Review
- Therapeutic targeting of the cGAS-STING pathway in human disease.The Journal of clinical investigation · 2026Review
- Advances in RPGR gene therapy for X‑linked retinitis pigmentosa: From preclinical insights to clinical application (Review).International journal of molecular medicine · 2026Review
- Article
- Development of cell-active BRD4-D1 selective inhibitors to decode the role of BET proteins in LPS-mediated liver inflammation.European journal of medicinal chemistry · 2026Article
- Targeted RNA Degradation by RIBOTACs: A Novel Therapeutic Avenue for Ophthalmic Diseases.International journal of molecular sciences · 2026Review
- Development and Characterization of a Noncovalent Stimulator of Interferon Genes Proteolysis-Targeting Chimeras.ChemMedChem · 2026Article
- cGAS-STING signaling pathway as a therapeutic target in human diseases.Chinese medical journal · 2025Review
- STING activates ZBP1-mediated PANoptosis to defend against HSV-1 retinal infection.Journal of neuroinflammation · 2025Article
- cGAS-STING pathway-mediated inflammatory response and its role in corneal fibrosis mechanisms.Molecular biology reports · 2025Review
- Targeting DNA damage in ageing: towards supercharging DNA repair.Nature reviews. Drug discovery · 2025Review
- Sorting nexin 3 promotes ischemic retinopathy through RIP1- and RIP3-mediated myeloid cell necroptosis and mitochondrial fission.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Triamcinolone Acetonide Protects Against Light-Induced Retinal Degeneration by Activating Anti-Inflammatory STAT6/Arg1 Signaling in Microglia.Inflammation · 2025Article
- Nicotinamide Riboside Mitigates Retinal Degeneration by Suppressing Damaged DNA-Stimulated Microglial Activation and STING-Mediated Pyroptosis.Investigative ophthalmology & visual science · 2025Article
- cGAMP promotes inner blood-retinal barrier breakdown through P2RX7-mediated transportation into microglia.Journal of neuroinflammation · 2025Article
- STING-targeting PROTACs: emerging therapeutic tools for enhanced immunotherapy in inflammatory diseases.Frontiers in immunology · 2025Review
- MMP-2-triggered, mitochondria-targeted PROTAC-PDT therapy of breast cancer and brain metastases inhibition.Nature communications · 2024Article
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Authors and funding
14 authors at 4 institutions in 1 country.
Funding
Abstract
backgroundChronic inflammation significantly contributes to photoreceptor death in blinding retinal diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). Bromodomain and extraterminal domain (BET) proteins are epigenetic readers that act as key proinflammatory factors. We recently found the first-generation BET inhibitor JQ1 alleviated sodium iodate-induced retinal degeneration by suppressing cGAS-STING innate immunity. Here, we investigated the effects and mechanism of dBET6, a proteolysis‑targeting chimera (PROTAC) small molecule that selectively degrades BET by the ubiquitin‒proteasome system, in light-induced retinal degeneration.
methodsMice were exposed to bright light to induce retinal degeneration, and the activation of cGAS-STING was determined by RNA-sequencing and molecular biology. Retinal function, morphology, photoreceptor viability and retinal inflammation were examined in the presence and absence of dBET6 treatment.
resultsIntraperitoneal injection of dBET6 led to the rapid degradation of BET protein in the retina without detectable toxicity. dBET6 improved retinal responsiveness and visual acuity after light damage (LD). dBET6 also repressed LD-induced retinal macrophages/microglia activation, Müller cell gliosis, photoreceptor death and retinal degeneration. Analysis of single-cell RNA-sequencing results revealed cGAS-STING components were expressed in retinal microglia. LD led to dramatic activation of the cGAS-STING pathway, whereas dBET6 suppressed LD-induced STING expression in reactive macrophages/microglia and the related inflammatory response.
conclusionsThis study indicates targeted degradation of BET by dBET6 exerts neuroprotective effects by inhibiting cGAS-STING in reactive retinal macrophages/microglia, and is expected to become a new strategy for treatment of retinal degeneration.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.