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The BET PROTAC inhibitor dBET6 protects against retinal degeneration and inhibits the cGAS-STING in response to light damage

Background: Chronic 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.

Methods: Mice 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.

Results: Intraperitoneal 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.

Conclusions: This 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.

 

Comments:

Your study investigated the effects and mechanism of dBET6, a proteolysis-targeting chimera (PROTAC) small molecule, in light-induced retinal degeneration. The background of the study highlights that chronic inflammation plays a significant role in photoreceptor death in retinal diseases such as age-related macular degeneration (AMD) and retinitis pigmentosa (RP). BET proteins, which are epigenetic readers and proinflammatory factors, are implicated in this process.

The first-generation BET inhibitor JQ1 has previously shown efficacy in alleviating retinal degeneration by suppressing the cGAS-STING innate immune pathway. Building on this knowledge, your study aimed to investigate whether dBET6, which selectively degrades BET proteins through the ubiquitin-proteasome system, could provide neuroprotective effects in light-induced retinal degeneration.

The methods involved exposing mice to bright light to induce retinal degeneration and assessing the activation of the cGAS-STING pathway through RNA-sequencing and molecular biology techniques. The study evaluated retinal function, morphology, photoreceptor viability, and retinal inflammation in the presence and absence of dBET6 treatment.

The results demonstrated that intraperitoneal injection of dBET6 effectively degraded BET proteins in the retina without causing detectable toxicity. Treatment with dBET6 improved retinal responsiveness and visual acuity following light damage. Furthermore, dBET6 reduced retinal macrophage/microglia activation, Müller cell gliosis, photoreceptor death, and overall retinal degeneration induced by light exposure.

Through single-cell RNA-sequencing analysis, it was discovered that the components of the cGAS-STING pathway were expressed in retinal microglia. Light exposure led to significant activation of the cGAS-STING pathway, while treatment with dBET6 suppressed the expression of STING (a component of the cGAS-STING pathway) in reactive macrophages/microglia, thereby reducing the related inflammatory response.

In conclusion, the study suggests that targeted degradation of BET proteins by dBET6 exerts neuroprotective effects by inhibiting the cGAS-STING pathway in reactive retinal macrophages/microglia. This finding indicates that dBET6 could potentially serve as a new therapeutic strategy for the treatment of retinal degeneration.

Related Products

Cat.No. Product Name Information
S8762 dBET6 dBET6 is a highly cell-permeable PROTAC degrader of BET bromodomains with an IC50 of 14 nM for BRD4 binding. dBET6 also induces c-MYC downregulation and apoptosis.

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Epigenetic Reader Domain Apoptosis related Myc