Usp38, an ubiquitin-specific protease, plays diverse roles in biological processes. It is involved in regulating protein stability through deubiquitination, participating in pathways like NF-κB and interacting with proteins crucial for cell growth, inflammation and viral resistance [1-10]. Genetic models, especially KO/CKO mouse models, are valuable in studying its functions.

In KO/CKO mouse models, Usp38 deficiency promotes IL-33-induced pro-inflammatory responses, increasing susceptibility to inflammatory damage, death and pulmonary fibrosis [1]. In the context of myocardial infarction, USP38-CKO reduces inflammatory markers, alleviates cardiac fibrosis, electrical and ion channel remodeling, and decreases susceptibility to ventricular arrhythmias by inhibiting the TAK1/NF-κB pathway [2]. Similarly, in atrial fibrillation after myocardial infarction, USP38-CKO attenuates atrial inflammation, fibrosis and AF susceptibility, while USP38-TG has the opposite effects [4]. In pressure-overload-induced heart failure, USP38 knockout decreases susceptibility to ventricular arrhythmias by shortening action potential duration and prolonging effective refractory period, and inhibiting TBK1/AKT/CAMKII signaling [3]. In pressure-overload-induced atrial fibrillation, USP38 knockout improves vulnerability to AF, while overexpression exacerbates it through NF-κB/NLRP3-mediated inflammatory responses [5].

In conclusion, Usp38 is a key regulator in inflammation, cardiac remodeling and arrhythmias. Studies using KO/CKO mouse models have significantly enhanced our understanding of its role in these disease areas, suggesting that Usp38 could be a potential therapeutic target for pulmonary fibrosis, cardiac remodeling and arrhythmias following myocardial infarction or heart failure [1-2, 4-5, 7].