PSMD3 (proteasome 26S subunit, non-ATPase 3) is a core component of the 26S proteasome's 19S regulatory complex, functioning in ATP-dependent degradation of ubiquitinated proteins and maintaining protein homeostasis 1. Beyond its canonical role in proteasomal protein degradation, PSMD3 has emerged as a multi-functional regulator with disease-specific roles. In cancer, PSMD3 functions as an oncogene: it stabilizes HER2 from degradation in breast cancer 1, stabilizes ILF3 to promote lung cancer cell proliferation and migration 2, and supports NF-κB activity driving TKI resistance in chr17 myeloid leukemia 3. High PSMD3 expression correlates with poor prognosis in FLT3-mutated acute myeloid leukemia 4. Beyond cancer, PSMD3 mutations cause pathological myopia through decreased expression and retinal pigment epithelial cell apoptosis 5, and PSMD3 downregulation contributes to dilated cardiomyopathy pathogenesis 6. PSMD3 is transcriptionally regulated by pluripotency factor Tex10, which binds H3K4me3-marked promoters to fine-tune Wnt signaling during spermatogenesis and primordial germ cell development 7. These findings position PSMD3 as both a therapeutic target in cancer and a gene whose dysfunction contributes to degenerative eye and heart disease.