USP2

USP2 is a ubiquitin-specific deubiquitinase that regulates protein ubiquitination, protein stability, and cellular proteostasis^[1][2]. Mechanistically, USP2 connects ubiquitin-proteasome signaling with cell survival, cell cycle control, circadian rhythm, metabolism, inflammation, antiviral response, and metastasis through substrates including Cyclin D1, PER1, CRY1, HDM2/p53, FASN, LDLR, TRAF6, TBK1, and TGFBR complexes^[1]. In disease models, USP2 elevation has been reported in glioma, testicular cancer, breast cancer, prostate cancer, inflammatory diseases, and hepatocellular carcinoma models^[1][3]. Compared with related isoforms, USP2a and USP2b show distinct biological roles: USP2a attenuates diabetes in adipose tissue macrophages, whereas USP2b aggravates type 2 diabetes and metabolic dysfunction-associated steatotic liver disease in hepatocytes^[4]. In hepatocellular carcinoma, USP2 stabilizes PPARγ, promotes fatty-acid biosynthesis and oleic acid production, and supports M2 macrophage polarization^[5]. For experimental applications, ML364 showed anticancer responses against HCC patient-derived organoids, while current USP2 inhibitors remain unapproved clinically and require improved specificity^[1][5].