USP18-STAT2 axis enhances hepatic resilience under proteotoxic stress

The liver is highly susceptible to proteotoxic stress because of its elevated protein turnover, yet the molecular mechanisms that preserve hepatocyte viability under proteostatic collapse remain incompletely understood. This study investigated whether basal type I interferon (IFN-I) signaling contributes to hepatic adaptation to proteotoxic stress and identified the molecular determinants underlying this response. Proteotoxic stress was induced in C57BL/6 mice, and HepG2 cells using the proteasome inhibitors bortezomib and MG132. Transcriptomic analysis, quantitative PCR, immunoblotting, immunofluorescence, biochemical fractionation, immunoprecipitation, site-directed mutagenesis, in vivo adenoviral gene delivery, and functional apoptosis assays were employed to define the regulation and function of IFN-I signalling during proteotoxic stress. Proteasomal inhibition suppressed basal IFN-I signaling by impairing IRF9 nuclear localization and downregulating a subset of interferon-stimulated genes (ISGs). Concurrently, ISGs, redistributed into detergent-insoluble aggregates. Among the ISGs examined, USP18 emerged as the principal determinant protecting hepatocytes from proteotoxic apoptosis. This cytoprotective effect was independent of its catalytic activity but required its scaffolding function mediated by isoleucine-60 and interaction with STAT2. USP18 formed reversible cytoplasmic condensates distinct from p62-positive aggresomes, while IFNα priming preserved soluble USP18, restored ISG expression, and markedly reduced proteotoxic injury both in cultured hepatocytes and in vivo. Genetic depletion or disruption of the USP18–STAT2 interaction abolished IFNα-mediated protection. Proteotoxic stress compromises hepatic resilience by suppressing basal IFN-I signaling through coordinated transcriptional repression and protein insolubility. The USP18–STAT2 axis functions as a non-canonical cytoprotective pathway that enhances hepatocyte survival independently of USP18 catalytic activity, identifying IFN-I signaling and USP18 as potential therapeutic targets for proteotoxic liver injury.