BRISC　(BRCC3　isopeptidase　complex)　is　a　deubiquitinating　enzyme　that　has　been　linked　with　inflammatory　processes,　but　its　role　in　liver　diseases　and　the　underlying　mechanism　are　unknown.　Here,　we　investigated　the　pathophysiological　role　of　BRISC　in　acute　liver　failure　using　a　mice　model　induced　by　D-galactosamine　(D-GalN)　plus　lipopolysaccharide　(LPS).　We　found　that　the　expression　of　BRISC　components　was　dramatically　increased　in　kupffer　cells　(KCs)　upon　LPS　treatment　in　vitro　or　by　the　injection　of　LPS　in　D-GalN-sensitized　mice.　D-GalN　plus　LPS-induced　liver　damage　and　mortality　in　global　BRISC-null　mice　were　markedly　attenuated,　which　was　accompanied　by　impaired　hepatocyte　death　and　hepatic　inflammation　response.　Constantly,　treatment　with　thiolutin,　a　potent　BRISC　inhibitor,　remarkably　alleviated　D-GalN/LPS-induced　liver　injury　in　mice.　By　using　bone　marrow-reconstituted　chimeric　mice　and　cell-specific　BRISC-deficient　mice,　we　demonstrated　that　KCs　are　the　key　effector　cells　responsible　for　protection　against　D-GalN/LPS-induced　liver　injury　in　BRISC-deficient　mice.　Mechanistically,　we　found　that　hepatic　and　circulating　levels　of　TNF-alpha,　IL-6,　MCP-1,　and　IL-1　beta,　as　well　as　TNF-alpha-　and　MCP-1-producing　KCs,　in　BRISC-deleted　mice　were　dramatically　decreased　as　early　as　1　h　after　D-GalN/LPS　challenge,　which　occurred　prior　to　the　elevation　of　the　liver　injury　markers.　Moreover,　LPS-induced　proinflammatory　cytokines　production　in　KCs　was　significantly　diminished　by　BRISC　deficiency　in　vitro,　which　was　accompanied　by　potently　attenuated　NF-kappa　B　activation.　Restoration　of　NF-kappa　B　activation　by　two　small　molecular　activators　of　NF-kappa　B　p65　effectively　reversed　the　suppression　of　cytokines　production　in　ABRO1-deficient　KCs　by　LPS.　In　conclusion,　BRISC　is　required　for　optimal　activation　of　NF-kappa　B-mediated　proinflammatory　cytokines　production　in　LPS-treated　KCs　and　contributes　to　acute　liver　injury.　This　study　opens　the　possibility　to　develop　new　strategies　for　the　inhibition　of　KCs-driven　inflammation　in　liver　diseases.