Ubiquitin-Specific Protease 7 (USP7) as a Promising Therapeutic Target for Drug Discovery: From Mechanisms to Therapies

Protein ubiquitination is a reversible post-translational modification regulated by ubiquitin-conjugating and deubiquitinating enzymes (DUBs). Ubiquitin-specific protease 7 (USP7), a well-characterized DUB, plays multifaceted roles in various cellular processes, making it a promising therapeutic target. The plasticity of its catalytic domain and unique allosteric regulation by substrates or external or intramolecular factors facilitate the identification of highly selective USP7 inhibitors. These inhibitors can engage distinct ubiquitin-binding sites through covalent or non-covalent mechanisms. Despite its therapeutic promise, no USP7 inhibitors have entered clinical trials, underscoring the urgent need for novel therapeutics. Here we provide a crystallographic and functional landscape of USP7's multilayer regulation and analyze the structure-activity relationship of inhibitors by chemotypes. Additionally, we explore USP7's roles in diseases and discuss the challenges in USP7-targeted drug discovery and future directions for therapeutic development. This Perspective aims to provide a systematic overview of USP7, from its regulatory mechanisms to its therapeutic potential.