BRCC3　isopeptidase　complex　(BRISC)　is　a　JAMM　subfamily　deubiquitinase　that　has　been　revealed　to　be　required　for　optional　activation　of　NLRP3　inflammasome　and　TLR4/NF-kappa　B　signaling　pathway.　BRISC　plays　an　important　role　in　lipopolysaccharide　(LPS)/D-galactosamine-induced　acute　liver　failure,　while　its　functional　contribution　to　alcoholic　liver　disease　(ALD)　is　still　unclear.　In　this　study,　we　found　that　the　expression　of　BRISC　components　was　increased　in　liver　tissues　of　alcoholic　hepatitis　(AH)　animal　models　and　patients　with　AH.　Mice　lacking　either　the　scaffold　subunit　ABRO1　or　the　catalytic　subunit　BRCC3　showed　attenuated　liver　steatosis,　inflammation,　and　liver　injury　compared　to　control　mice　after　chronic　plus　binge　ethanol　feeding.　Moreover,　pharmacological　inhibition　of　BRISC　activity　by　a　BRISC　inhibitor　thiolutin　potently　protected　mice　from　ALD　development.　Preliminary　mechanistical　studies　showed　that　BRISC　deficiency　did　not　directly　affect　alcohol-induced　hepatocyte　injury　or　the　translocation　of　LPS　through　the　damaged　gut　mucosa　after　ethanol　feeding,　but　prevented　alcohol-induced　NLRP3　inflammasome　activation　in　liver.　Collectively,　our　work　revealed　a　previously　unknown　role　of　BRISC　in　ALD　and　suggested　that　BRISC　may　serve　as　a　promising　therapeutic　target　for　ALD　treatment.