| 描述信息 |
Uveitis is a sight-threatening intraocular inflammation in which the pro-inflammatory immune response driven by retinal microglia is a key contributor. Proteolysis targeting chimera (PROTAC) targeting bromodomain and extraterminal (BET) proteins have 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 pro-inflammatory 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 pro-inflammatory 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 pro-inflammatory microglia in autoimmune uveitis, potentially providing a new therapeutic approach for uveitis. |
