PSMC3 (proteasome 26S subunit, ATPase 3) is an essential component of the 26S proteasome complex that plays critical roles in protein homeostasis and cellular regulation 1. As part of the heterohexameric AAA-ATPase ring, PSMC3 functions in ATP-dependent unfolding and translocation of ubiquitinated proteins into the proteolytic chamber for degradation 1. The protein facilitates proteasome-mediated degradation of specific targets, including the transcription factor FRA1 when its ADP-ribosylation is disrupted 2 and NRF2 through ubiquitin-dependent pathways in glioblastoma cells 3. PSMC3 also maintains AGO2 stability by facilitating USP14-mediated deubiquitination, thereby promoting RNA interference activity 4. During spermatogenesis, PSMC3 localizes to acrosomal membranes and head-tail coupling apparatus, suggesting roles in sperm development 5. De novo missense variants in PSMC3 cause autosomal dominant neurodevelopmental delay and intellectual disability, associated with proteasome dysfunction, proteotoxic stress, and dysregulated type I interferon signaling through PKR activation 1. PSMC3 variants have also been implicated in lacunar stroke susceptibility 6 and human well-being spectrum traits 7, highlighting its broad physiological importance.