Otud3, short for ovarian-tumor-domain-containing deubiquitinase 3, is a crucial deubiquitinase. It blocks ubiquitin-dependent protein degradation, participates in diverse signaling pathways, and is involved in regulating various physiological and pathological processes such as immunity, inflammation, metabolism, and tumorigenesis [1,2,3].

Otud3-/-mice developed worse obesity, dyslipidemia, and insulin resistance than wild-type mice when challenged with a high-fat diet, indicating its role in metabolism homeostasis. Targeting PPARδ using a specific agonist could partially rescue the phenotype of HFD-fed Otud3-/-mice, suggesting OTUD3 regulates genes involved in glucose and lipid metabolism and oxidative phosphorylation by stabilizing PPARδ [1].

In cancer, OTUD3 shows cell-and tissue-dependent roles. For example, in breast cancer, its deletion promotes cancer development, while in KrasG12D-driven lung adenocarcinoma, its deletion slows down tumor initiation and progression [4]. In liver cancer, OTUD3 deficiency in mice leads to enhanced integrated stress response and accelerated tumor progression [5].

In conclusion, Otud3 is an important regulator of energy metabolism and plays a cell-and tissue-specific role in tumorigenesis. The use of Otud3 knockout mouse models has significantly contributed to understanding its functions in metabolism-related diseases and cancer, providing insights into potential therapeutic targets for these conditions.