BRCC3, also known as BRCA1-BRCA2-containing complex subunit 3, is a JAMM domain-containing Zn2+ metalloprotease deubiquitinating enzyme. It modifies the activity and stability of substrate proteins through K63-dependent deubiquitination, and is involved in multiple biological pathways such as BMP/TGF-β, NLRP3/NLRP6 inflammasome, and NF-κB signaling pathways, playing a crucial role in maintaining normal physiological functions and disease-related processes [1-10].

In pulmonary hypertension, Brcc3-/-mice showed increased susceptibility to experimental pulmonary hypertension due to inhibition of the ALK2-Smad1/5 signaling, indicating that BRCC3 is pivotal in maintaining pulmonary vascular homeostasis by balancing BMP and TGF-β signaling in pulmonary artery smooth muscle cells [1]. In Tet2 clonal hematopoiesis-related atherosclerosis, holomycin, a BRCC3 deubiquitinase inhibitor, reversed accelerated atherosclerosis in Tet2 CH mice, suggesting BRCC3-mediated NLRP3 deubiquitylation promotes inflammasome activation and atherosclerosis [3]. In colitis, CD82 deficiency improved colitis by increasing NLRP3 deubiquitination by BRCC3 [4]. In cerebral ischemia/reperfusion injury, BRCC3 knockdown reduced inflammation, pyroptosis, and neurological deficits in mice [2,5].

In conclusion, BRCC3 is essential in multiple biological processes and disease conditions. The study of BRCC3 through gene knockout (KO) or conditional knockout (CKO) mouse models has revealed its roles in pulmonary hypertension, atherosclerosis, colitis, and cerebral ischemia/reperfusion injury, providing valuable insights into disease mechanisms and potential therapeutic targets.