Usp18, also known as UBP43, is a deubiquitinase (DUB) that specifically removes the ubiquitin-like protein ISG15 from target proteins, a process called deISGylation. It is a key regulator in the type I interferon signaling pathway, with its actions having a significant impact on immune responses, and is thus of great biological importance. Genetic models, such as KO/CKO mouse models, have been crucial in studying its functions [6,7,8].

Mice deficient in USP18 are more susceptible to RNA virus infection, indicating that USP18 positively regulates innate antiviral immunity by promoting K63-linked polyubiquitination of MAVS, an adaptor molecule in Rig-I-like receptor (RLR) signaling [1]. USP18 also plays a role in the replication of HIV-1. HIV-1 infection induces USP18, which enhances HIV-1 replication by abrogating the antiviral function of p21 [2]. In addition, USP18 antagonizes pyroptosis by facilitating the selective autophagic degradation of Gasdermin D, a key executioner of pyroptosis [3]. USP18, along with the CRL3KCTD10 ubiquitin ligase, coordinately regulates cystine uptake and ferroptosis by modulating SLC7A11, a cystine transporter and ferroptosis inhibitor [4]. Depletion of USP18 selectively induces cancer cell immunogenic cell death (ICD), and lower USP18 expression correlates with better survival across selected human cancer types and delays cancer progression in mouse models [5].

In conclusion, USP18 is a multifunctional protein involved in various biological processes. Model-based research, especially using KO/CKO mouse models, has revealed its important roles in antiviral immunity, viral replication, pyroptosis, ferroptosis, and cancer. These findings provide insights into the mechanisms of related diseases and potential therapeutic targets.