USP30 Beyond Mitophagy: A Context-Dependent Deubiquitinase in Cancer Progression

Ubiquitin-specific protease 30 (USP30) is a mitochondrial outer membrane-associated deubiquitinase best known for antagonizing PTEN-induced kinase 1 (PINK1)/Parkin-dependent ubiquitination and suppressing mitophagy. This established role has linked USP30 to mitochondrial quality control and neurodegenerative diseases. However, emerging studies in cancer have expanded the biological scope of USP30, revealing functions that cannot be explained by mitophagy regulation alone. USP30 regulates diverse cancer-associated substrates through deubiquitination, thereby affecting protein abundance, subcellular localization, protein interactions, and downstream transcriptional programs. These substrate-dependent effects influence mitochondrial dynamics, lipid synthesis, glucose and amino acid metabolism, redox homeostasis, apoptosis, ferroptosis, epithelial-mesenchymal transition, cancer stemness, T-cell exhaustion, and therapy resistance. Although most studies indicate tumor-promoting roles of USP30 in hepatocellular carcinoma, breast cancer, colorectal cancer, oral squamous cell carcinoma, ovarian cancer, bladder cancer, prostate cancer, and leukemia models, context-dependent tumor-restraining activities have also been reported. In this Review, we examine cancer-associated functions of USP30 that extend beyond its established role in PINK1/Parkin-dependent mitophagy, discuss the spatial and substrate-dependent mechanisms underlying these activities, and highlight opportunities and challenges for therapeutic targeting.