Otud1, an ovarian tumor protease (OTU) family deubiquitinase, contains an N-terminal-disordered alanine -, proline -, glycine-rich region (APGR), a catalytic OTU domain, and a ubiquitin-interacting motif (UIM). It preferentially hydrolyzes lysine-63-linked ubiquitin chains and is involved in multiple cellular functions, regulating various pathways such as NF-κB, KEAP1-NRF2, and Notch2-ICD. It also plays a role in many biological processes including inflammation, immune responses, oxidative stress, and apoptosis, thus being crucial for maintaining cellular homeostasis [5,6].

In gene knockout mouse models, OTUD1 deficiency has shown diverse effects. In cardiac remodeling, OTUD1 knockout mice were protected against angiotensin II-induced cardiac dysfunction, hypertrophy, fibrosis, and inflammatory response, indicating that OTUD1 promotes pathological cardiac remodeling by deubiquitinating STAT3 [1]. In periodontitis, neutrophil-intrinsic OTUD1 depletion induced severe periodontitis, suggesting OTUD1 suppresses secretory neutrophil polarization [2]. In colonic inflammation, loss of OTUD1 in mice contributed to the pathogenesis of dextran sulfate sodium-induced colitis [3]. Also, OTUD1 deficiency exacerbated cerebral ischemic injury [4].

In conclusion, Otud1 is a key regulator in multiple biological processes. The use of Otud1 KO mouse models has revealed its significant roles in diseases such as cardiac remodeling, periodontitis, colonic inflammation, and cerebral ischemia. Understanding Otud1's functions provides potential therapeutic targets for these disease areas.