PSMF1 (proteasome inhibitor subunit 1) is a conserved proteasome regulator that antagonistically controls 20S proteasomal activity 1. It directly interacts with VCP to regulate protein degradation pathways critical for cellular homeostasis 1. PSMF1 inhibits both the hydrolysis of protein substrates by the 20S proteasome and activation by regulatory proteins PA700 and PA28, functioning as a negative regulator of proteasomal protein catabolism 2. Clinically, PSMF1 has emerged as a significant neurodegeneration gene. Biallelic variants cause a phenotypic spectrum from early-onset Parkinson's disease to perinatal lethality with neurological manifestations 2. Pathogenic PSMF1 variants impair mitochondrial membrane potential, dynamics, and mitophagy, with Drosophila and mouse models showing age-dependent motor impairment and dopaminergic neurodegeneration 2. PSMF1 represents a newly identified autosomal recessive early-onset Parkinson's disease gene 3. In cancer biology, mutant TP53 transcriptionally activates PSMF1 to increase organoid resistance to endoplasmic reticulum stress, implicating it in hepatocellular carcinoma pathogenesis 4. Additionally, PSMF1 variants predict non-small cell lung cancer survival through MHC-I antigen presentation pathways 5, and the gene appears enriched among stemness-associated immunotherapy targets 6.