Usp30, short for Ubiquitin-specific protease 30, is a deubiquitinating enzyme belonging to the USP subfamily. It localizes in the mitochondrial outer membrane and peroxisomes due to its unique transmembrane domain. Usp30 plays essential roles in multiple cellular events such as PINK1/Parkin-mediated mitophagy, pexophagy, BAX/BAK-dependent apoptosis, and IKKβ-USP30-ACLY-regulated lipogenesis/tumorigenesis. It is also tightly regulated by post-translational modifications [1].

Knockdown of Usp30 in dopaminergic neurons of flies protects against paraquat toxicity, ameliorating defects in dopamine levels, motor function, and organismal survival. It also rescues defective mitophagy caused by pathogenic mutations in parkin and improves mitochondrial integrity in parkin-or PINK1-deficient flies, suggesting its potential role in Parkinson's disease [2]. In mice, deletion of Usp30 attenuated lipogenesis, inflammation, and tumorigenesis in DEN/CCl4-treated mice, indicating its role in hepatocellular carcinoma [3]. Usp30 knockout mice show protection against behavioral deficits, increased mitophagy, decreased phospho-S129 αSyn, and attenuation of SN dopaminergic neuronal loss induced by αSyn, further supporting the potential of Usp30 inhibition in Parkinson's disease [4].

In conclusion, Usp30 is crucial in regulating cellular events related to mitochondrial function, apoptosis, and lipogenesis. Studies using gene knockout models, especially in mouse models, have revealed its significant roles in neurodegenerative diseases like Parkinson's and in hepatocellular carcinoma. These findings highlight the potential of targeting Usp30 for therapeutic interventions in these disease areas.