Otud5, an ovarian tumor (OTU) deubiquitinase, is a functional cysteine protease with deubiquitinase activity, belonging to the OTU family. It is involved in the deubiquitination of key proteins in multiple cellular signaling pathways, playing a crucial role in maintaining normal human development and physiological functions [6]. Dysfunction of Otud5 can impact immunity, DNA damage repair, and may lead to diseases like tumors, inflammatory diseases, and genetic disorders. Gene knockout (KO) and conditional knockout (CKO) mouse models are valuable for studying its functions.

In myocardial ischemia/reperfusion (MI/R) injury, 4-hydroxy-2-nonenal (4-HNE) accumulates, triggering ferroptosis. Otud5 loss-of-function exacerbates this, while its elevation deubiquitinates and stabilizes glutathione peroxidase 4 (GPX4), reversing 4-HNE-induced ferroptosis and alleviating MI/R injury [1].

In the kidney, during ischemia-reperfusion (I/R), mTORC1-mediated autophagy causes Otud5 degradation, leading to GPX4 decay and ferroptosis. Otud5 deletion intensifies renal tubular cell ferroptosis and acute kidney injury, while AAV-mediated Otud5 delivery mitigates ferroptosis and promotes renal function recovery [2].

In podocytes, podocyte-specific Otud5 knockout exacerbates podocyte injury and diabetic kidney disease (DKD) in both type 1 and type 2 diabetic mice, while AVV9-mediated Otud5 overexpression shows a therapeutic effect against DKD [3].

In innate immunity, knockout of Otud5 in Lyz2-Cre Otud5fl/Y and CD11-Cre Otud5fl/Y mice impairs type I IFN signaling, making them more susceptible to herpes simplex virus type 1 (HSV-1) infection and melanoma development [4].

In sepsis, Otud5-deficient mice are less susceptible to LPS-and CLP-induced sepsis as Otud5 promotes MyD88 oligomerization and Myddosome formation to enhance the inflammatory immune response [5].

In hepatocellular carcinoma (HCC), OTUD5 knockdown suppresses HCC cell proliferation and growth in vivo, as it promotes HCC cell proliferation by deubiquitinating and stabilizing SLC38A1 [7].

In bladder cancer, OTUD5 promotes cancer progression through the OTUD5-RNF186-sestrin2-mTOR axis [8]. Knockdown of OTUD5 accelerates tumor growth in a nude mouse model, as it regulates gene transcription and suppresses tumorigenesis by deubiquitinating TRIM25 [9].

In conclusion, Otud5 is essential in multiple biological processes and diseases. Through KO/CKO mouse models, it has been revealed to play important roles in ferroptosis-related injuries in the heart and kidney, podocyte-related DKD, innate antiviral and antitumor immunity, inflammatory immune response, and the progression of certain cancers. Understanding Otud5's functions provides potential therapeutic targets for these diseases.