PSMD14 is a metalloprotease component of the 26S proteasome that specifically cleaves K63-linked polyubiquitin chains and serves multiple cellular functions beyond protein degradation 1. As a deubiquitinase, PSMD14 regulates DNA damage repair by promoting both non-homologous end joining and homologous recombination pathways through K63-linked polyubiquitin cleavage 1. The protein also controls macroautophagy by ensuring proper Golgi-to-ER retrograde transport through deubiquitination of K63-linked ubiquitin chains 2. Beyond its proteasomal role, PSMD14 functions as an epigenetic regulator, acting as a histone H2AK119 deubiquitinase that facilitates NSD2-directed H3K36 dimethylation and forms a positive feedback loop with RELA in myeloma pathogenesis 3. In cancer contexts, PSMD14 promotes tumor progression through multiple mechanisms: stabilizing metabolic enzymes like PKM2 and SLC7A11 45, enhancing lipid synthesis via LDHA stabilization and histone lactylation 6, and facilitating alternative splicing through SF3B4 stabilization 7. High PSMD14 expression correlates with poor prognosis across multiple cancer types, making it an attractive therapeutic target 8. The protein's diverse functions span from maintaining cellular homeostasis to driving oncogenic processes, highlighting its critical role in both normal physiology and disease pathogenesis.