biostudies-literatureChowdhury SCouncil of Scientific and Industrial ResearchCouncil of Scientific and Industrial Research (CSIR)405https://www.ebi.ac.uk/biostudies/studies/S-EPMC11405666biostudies-literatureUnknown10(1)Derangements in protein homeostasis and associated proteotoxicity mark acute, chronic, and drug-induced hepatocellular injury. Metabolic dysfunction-associated proteasomal inhibition and the use of proteasome inhibitors often underlie such pathological hepatic proteotoxicity. In this study, we sought to identify a candidate deubiquitinating enzyme (DUB) responsible for reversing the proteotoxic damage. To this end, we performed a siRNA screening wherein 96 DUBs were individually knocked down in HepG2 cells under proteasomal inhibitor-induced stress for dual readouts, apoptosis, and cell viability. Among the putative hits, we chose JOSD1, a member of the Machado-Josephin family of DUBs that reciprocally increased cell viability and decreased cell death under proteotoxicity. JOSD1-mediated mCell death discoveryDeubiquitinase JOSD1 tempers hepatic proteotoxicity.PMC11405666MLP138Das DChowdhury SChakrabarti PSen AfalseDeubiquitinase JOSD1 tempers hepatic proteotoxicity.Derangements in protein homeostasis and associated proteotoxicity mark acute, chronic, and drug-induced hepatocellular injury. Metabolic dysfunction-associated proteasomal inhibition and the use of proteasome inhibitors often underlie such pathological hepatic proteotoxicity. In this study, we sought to identify a candidate deubiquitinating enzyme (DUB) responsible for reversing the proteotoxic damage. To this end, we performed a siRNA screening wherein 96 DUBs were individually knocked down in HepG2 cells under proteasomal inhibitor-induced stress for dual readouts, apoptosis, and cell viability. Among the putative hits, we chose JOSD1, a member of the Machado-Josephin family of DUBs that reciprocally increased cell viability and decreased cell death under proteotoxicity. JOSD1-mediated m2024-01-01T00:00:00Z2024 Sep2025-04-05T18:45:16.888Z2025-04-05T18:45:16.888ZS-EPMC114056663928483010.1038/s41420-024-02177-y