USP42 is a cysteine-type deubiquitinase that regulates protein stability through multiple cellular mechanisms. Functionally, USP42 catalyzes histone H2B deubiquitylation to regulate transcriptional activity independently of p53 1, and directs nuclear speckle phase separation to organize mRNA splicing machinery, particularly through PLRG1 integration 2. USP42 stabilizes diverse substrates including PPARγ in hepatocytes 3, and TRIM21/OAS1 in immune responses 4. Disease relevance is substantial across multiple malignancies. In gastric cancer, elevated USP42 correlates with tumor size, TNM stage, lymph node metastasis, and poor survival; USP42 silencing inhibits proliferation and invasion via matrix metalloproteinase/EMT regulation 5. In breast cancer, USP42 promotes progression by suppressing JNK/p38-mediated apoptosis, with expression correlating to advanced stage 6. USP42 also drives non-small-cell lung cancer through nuclear speckle-dependent splicing 2. Notably, RUNX1-USP42 fusion genes occur in acute myeloid leukemia through cryptic chr7 rearrangements 78, suggesting deregulated ubiquitin pathways contribute to leukemogenesis. Clinically, USP42 inhibition represents a novel anticancer strategy 2, while USP42-PPARγ axis activation shows therapeutic promise for liver regeneration and oxidative injury protection 3.