泛素特异性蛋白酶30（USP30）是定位于线粒体外膜与过氧化物酶体的关键去泛素化酶，通过调控线粒体自噬维持细胞器稳态，这一机制的失调已被证实是帕金森病、阿尔茨海默病等神经退行性疾病发生发展的核心环节。系统梳理USP30的分子结构特征与生物学功能，按结构类型对现有USP30抑制剂进行分类评述。在此基础上，深入剖析当前USP30抑制剂开发面临的靶点选择性、血脑屏障穿透性及临床转化瓶颈等关键挑战，为下一代高选择性USP30抑制剂的理性设计与临床前开发提供策略指引。

Ubiquitin-specific protease 30 (USP30) is a deubiquitinase anchored to the outer mitochondrial membrane and peroxisomes, where it serves as a critical checkpoint in regulating mitophagy and preserving organelle homeostasis. The dysregulation of this qualitycontrol machinery has emerged as a pivotal driver in the pathogenesis of neurodegenerative disorders, including Parkinson’s and Alzheimer’s diseases. This review provides a systematic characterization of the molecular architecture and biological functions of USP30, alongside a classified evaluation of existing inhibitors stratified by their chemotypes. Crucially, we dissect the prominent bottlenecks impeding clinical translation—specifically off-target effects, blood-brain barrier (BBB) permeability, and pharmacokinetic limitations. By synthesizing current structure-activity relationships and addressing these developmental hurdles, this review offers strategic insights for the rational design of next-generation, high-selectivity USP30 inhibitors, highlighting their therapeutic potential in combating neurodegenerative pathologies.

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