USP30

Class

mitochondrial deubiquitinase inhibitor

USP30 is a deubiquitinating enzyme (DUB) anchored to the outer mitochondrial membrane. Its normal job is to remove ubiquitin tags from mitochondrial surface proteins, counteracting the PINK1/Parkin quality-control pathway that marks damaged mitochondria for selective degradation, a process called mitophagy. When mitochondria are injured, cells rely on ubiquitin tagging to flag them for clearance; USP30 acts as a brake on this system by stripping those tags off. Inhibiting USP30 shifts the balance toward more efficient removal of damaged mitochondria, which is of interest wherever impaired mitophagy and accumulation of dysfunctional mitochondria contribute to disease. This includes neurodegenerative conditions such as Parkinson's disease, where mutations in PINK1 or Parkin itself impair mitochondrial clearance, as well as kidney injury and certain fibrotic or inflammatory conditions linked to mitochondrial stress and dysfunction. Because USP30 inhibition works downstream of these upstream regulators, it offers a pharmacological way to boost mitophagy even when the primary drivers of mitochondrial damage lie elsewhere. As a small-molecule-druggable enzyme with a defined catalytic pocket, USP30 is amenable to selective inhibitor design, distinguishing it from broader, less specific strategies aimed at mitochondrial quality control.