USP2 is a deubiquitinating enzyme that functions as a circadian clock output effector regulating calcium absorption in the small intestine [UniProt]. Mechanistically, USP2 stabilizes target proteins through K48-linked polyubiquitin chain removal, including the membrane scaffold protein NHERF4, which controls calcium channel TRPV6 permeability in intestinal epithelium [UniProt]. Beyond circadian regulation, USP2 plays multifaceted roles in disease pathology. In cancer immunoevasion, USP2 stabilizes PD-L1 and CD47, promoting tumor immune escape; USP2 inhibition destabilizes these immune checkpoint proteins and enhances anti-tumor immunity 12. USP2 also stabilizes E2F4 to drive autophagy-dependent zinc homeostasis in gastric cancer 3 and stabilizes FASN to promote osteosarcoma progression via autophagy activation 4. In metabolic disease, USP2 exerts context-dependent effects: it stabilizes PPARγ to promote hepatic lipid accumulation in metabolic dysfunction-associated steatotic liver disease (MASLD) and hepatocellular carcinoma, driving disease progression and M2 macrophage polarization 56. Conversely, USP2 in adipose tissue macrophages and hypothalamus improves hyperglycemia 7. These contrasting roles highlight USP2's tissue-specific regulatory functions in metabolic homeostasis and disease.