{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nUbiquitin‐specific protease 18 (USP18) is a multifaceted regulator of innate immunity that exerts dual functions. On the one hand, it is the sole deconjugating enzyme that specifically removes the ubiquitin‐like modifier ISG15 from its substrates, and on the other, it acts in a non‐catalytic manner to negatively regulate type I interferon (IFN) signaling. Inherited loss‐of‐function mutations lead to uncontrolled IFN responses—as illustrated in disorders such as pseudo‐TORCH syndrome—highlighting its indispensable role in constraining detrimental inflammatory cascades and preserving central nervous system homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "5"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its canonical role, USP18 modulates antiviral and inflammatory signaling pathways by interacting with key mediators. For instance, it is recruited via STAT2 to the IFN receptor to enforce feedback inhibition and interferes with the assembly and stabilization of receptor subunits, thereby modulating downstream responses. Moreover, by engaging with signaling scaffolds and deubiquitinating regulators involved in NF‐κB activation, USP18 helps balance pro‐inflammatory mediator production and antiviral effector functions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "6", "end_ref": "8"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nUSP18 also influences oncogenesis and cell survival. In various cancer models, it limits susceptibility to IFN‐induced apoptosis and modulates critical growth‐ and survival‐promoting pathways. Mechanistically, USP18 regulates the expression and stability of oncogenic drivers such as the epidermal growth factor receptor (EGFR), affects microRNA networks (e.g. miR‐7) and maintains pro‐survival signals via the AKT/Skp2 axis. Its function is further intertwined with ubiquitination machinery (e.g. Skp2) and the stability of tumor suppressors (such as PTEN), collectively fostering tumor growth, promoting metastasis and contributing to chemoresistance."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "15"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMoreover, altered USP18 activity is implicated in metabolic and autoimmune disorders. In pancreatic β‐cells, dysregulated USP18 accentuates IFN‐mediated inflammation and apoptosis contributing to type 1 diabetes, while in hepatocytes its modulation of TAK1 deubiquitination improves lipid metabolism, ameliorating aspects of nonalcoholic fatty liver disease. In the setting of autoimmune skin disorders, oxidative stress induces epigenetic silencing of USP18, thereby enhancing ISG15 expression and triggering pathogenic T‐cell responses. In the realm of infectious diseases, USP18 governs viral replication and host defenses against pathogens such as hepatitis B, HIV‐1 and influenza by modulating key factors—including p21, SAMHD1 and components of the cGAS–STING pathway—and by influencing intracellular dNTP pools and the stability of antiviral effectors. Complementary studies addressing its regulation in immune cells, translational control mechanisms and structural determinants of its ISG15 specificity further underline its potential as a therapeutic target in multiple sclerosis, lymphomas and even latent infections."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "38"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marije E C Meuwissen, Rachel Schot, Sofija Buta, et al. 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