Usp30, or Ubiquitin-specific protease 30, is a deubiquitinating enzyme in the USP subfamily. It localizes to the mitochondrial outer membrane and peroxisomes due to its transmembrane domain. It plays essential roles in multiple cellular events like PINK1/Parkin-mediated mitophagy, pexophagy, BAX/BAK-dependent apoptosis, and IKKβ-USP30-ACLY-regulated lipogenesis/tumorigenesis [1].

In hepatocellular carcinoma (HCC), IKKβ phosphorylates and stabilizes USP30, which deubiquitinates ATP citrate lyase (ACLY) and fatty acid synthase (FASN), promoting lipogenesis and tumorigenesis. Deletion of USP30 in DEN/CCl4-treated mice attenuates lipogenesis, inflammation, and tumorigenesis [2].

In Parkinson's disease-related studies, USP30 opposes parkin-mediated mitophagy. Overexpression of USP30 blocks parkin-driven mitophagy, while reducing its activity enhances mitochondrial degradation in neurons. Knockdown of USP30 rescues defective mitophagy caused by parkin mutations in flies and protects dopaminergic neurons in flies against paraquat toxicity [3]. In a Parkinson's disease mouse model, loss of USP30 in Usp30 knockout mice protects against behavioral deficits, increases mitophagy, decreases phospho-S129 αSyn, and attenuates SN dopaminergic neuronal loss induced by αSyn. These effects were also seen with a USP30 inhibitor [4].

In conclusion, Usp30 is crucial in regulating mitophagy, apoptosis, lipogenesis, and tumorigenesis. The use of Usp30 knockout mouse models has significantly contributed to understanding its role in diseases such as hepatocellular carcinoma and Parkinson's disease, providing potential therapeutic targets for these conditions.