Frederick et al. (1998) obtained the first evidence of the link between USP4 and cancer when they demonstrated the lower expression of USP4 in small cell lung cancer and squamous cell lung cancer compared with normal samples. Since then, numerous studies have documented USP4 to function as an oncoprotein or a tumor repressor in a range of different cancer types. USP4 was also reported to have impacts on many other pathological contexts, such as viral and bacterial infections, acute injury and inflammation, chronic fibrosis-related diseases, metabolic disorders, and immune disease (Table 3). Here, USP4 is linked to metabolic disease.