Otud1, an ovarian tumor protease (OTU) family deubiquitinating enzyme (DUB), has 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 regulating multiple cellular functions, including immune responses, apoptosis, and oxidative stress responses. It is associated with pathways like NF-κB, KEAP1-NRF2, and STAT3 signaling, playing a crucial role in various biological processes and disease conditions. Genetic models, such as knockout mice, have been instrumental in studying its functions [5].

In mouse models, Otud1 knockout significantly protected against angiotensin II-induced cardiac dysfunction, hypertrophy, fibrosis, and inflammatory response, as well as transverse aortic constriction-induced cardiac remodeling, indicating its role in promoting pathological cardiac remodeling by deubiquitinating STAT3 [1]. In periodontitis mouse models, depletion of neutrophil-intrinsic Otud1 induced severe periodontitis, suggesting it suppresses secretory neutrophil polarization [2]. In dextran sulfate sodium-induced colitis mouse models, loss of Otud1 contributed to the pathogenesis via excessive release of pro-inflammatory cytokines, showing its role in inhibiting colonic inflammation [3]. In cerebral ischemia mouse models, Otud1 deficiency exacerbated cerebral ischemic injury, demonstrating its role in ameliorating cerebral ischemic injury through inhibiting RIP2-induced NF-κB activation [4]. In hepatic ischemia/reperfusion injury mouse models, Otud1 alleviated oxidative stress, apoptosis, and inflammation by deubiquitinating and activating NRF2 [6]. In acute graft-versus-host disease (aGVHD) mouse models, Otud1 was essential for aGVHD as it promoted the differentiation and functions of Th1 and Th17 cells [7].

In conclusion, Otud1 is a crucial regulator in multiple biological processes. Model-based research, especially using Otud1 KO mouse models, has revealed its role in various disease areas such as heart failure, periodontitis, colonic inflammation, cerebral ischemia, hepatic ischemia/reperfusion injury, and aGVHD. Understanding Otud1 functions provides insights into disease mechanisms and potential therapeutic targets.