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

  • iScience. 2025 Dec 22;29(2):114526. doi: 10.1016/j.isci.2025.114526.
Zhi Zhang  1  2  3 ,  Tianlong Lan  4 ,  Yongbo Liu  4 ,  Hui Yang  2 ,  Nan Shu  3 ,  Ruonan Li  1 ,  Wanqian Li  1 ,  Qian Zhou  1 ,  Peizeng Yang  1 ,  Yu Rao  4 ,  Shengping Hou  2
Affiliations
  • 1. Chongqing Key Laboratory of Ophthalmology, Chongqing Eye Institute, Chongqing Branch of National Clinical Research Center for Ocular Diseases, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  • 2. Beijing Institute of Ophthalmology, Beijing Tongren Eye Center, Beijing Ophthalmology & Visual Sciences Key Laboratory, Beijing Tongren Hospital, Capital Medical University, Beijing 100730, China.
  • 3. Chongqing Medical and Pharmaceutical College, Chongqing 401331, China.
  • 4. MOE Key Laboratory of Protein Sciences, School of Pharmaceutical Sciences, MOE Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology, Tsinghua University, Beijing 100084, China.
PMID: 41585484 DOI: 10.1016/j.isci.2025.114526
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.

Keywords
Biological sciences; Epigenetics; Ophthalmology.
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