# BRD3 PROTAC degrader targets H3K18ac to alleviate retinal microglia-driven uveitis

## TL;DR

A PROTAC called D072 reduces inflammation in retinal microglia by degrading BRD3, potentially offering a new treatment for uveitis.

## Contribution

D072 is a specific BRD3 degrader that alleviates uveitis by modulating H3K18ac and proinflammatory gene activity.

## Key findings

- PROTAC D072 reduces intraocular inflammation and inhibits proinflammatory microglia in uveitis.
- BRD3 degradation by D072 leads to reduced H3K18ac and altered chromatin states of inflammation-related genes.
- HDACs partially regulate H3K18ac levels following BRD3 degradation, affecting CCL5 signaling.

## Abstract

Uveitis is a sight-threatening intraocular inflammation in which the proinflammatory immune response driven by retinal microglia is a key contributor. Proteolysis targeting chimera (PROTAC) targeting bromodomain and extraterminal (BET) proteins has shown therapeutic effects in certain inflammatory diseases or tumors, but their effects on uveitis remain elusive. Our research demonstrated that PROTAC D072 reduced intraocular inflammation in vivo and inhibited proinflammatory microglia in both uveitis retina and lipopolysaccharide (LPS) treated mouse microglia cell line BV2. Drug target verification revealed that D072 specifically degraded BRD3 but did not significantly affect BRD2 or BRD4. Mechanistically, BRD3 degradation resulted in reduced H3K18ac, and CUT&Tag analysis revealed changes in the occupancy of several proinflammatory and metabolism-related genes. Furthermore, histone deacetylases (HDACs) partially regulate the H3K18ac level following BRD3 degradation. Overall, we identified D072 as a specific degrader of BRD3 in the murine system that can inhibit proinflammatory microglia in autoimmune uveitis, potentially providing a therapeutic approach for uveitis.

•A PROTAC named D072 selectively degrades BRD3 in mice•BRD3 is involved in the proinflammatory process of retinal microglia in EAU•BRD3-H3K18ac modulated chromatin state of inflammation and metabolism gene•HDAC-driven H3K18ac change controlled by BRD3 to inhibit CCL5 signaling

A PROTAC named D072 selectively degrades BRD3 in mice

BRD3 is involved in the proinflammatory process of retinal microglia in EAU

BRD3-H3K18ac modulated chromatin state of inflammation and metabolism gene

HDAC-driven H3K18ac change controlled by BRD3 to inhibit CCL5 signaling

Ophthalmology; Biological sciences; Epigenetics