PSME4 (proteasome activator subunit 4) is a proteasome regulator that recognizes acetylated histones through its bromodomain-like region and promotes ATP- and ubiquitin-independent histone degradation. It functions by binding the proteasomal core via its C-terminus, opening the gated channel for substrate entry through an active gating mechanism. PSME4 plays dual roles: during spermatogenesis, it participates in histone exchange within the spermatoproteasome complex [UniProt annotation], and in somatic cells, it promotes histone degradation following DNA double-strand breaks as part of the DNA damage response. In cancer biology, PSME4 upregulation in non-small-cell lung carcinoma attenuates antigenic diversity and associates with immunotherapy resistance 1. In multiple myeloma, PSME4 is overexpressed in relapsed/refractory disease and represents a therapeutic target 2. PSME4 dysregulation has been identified as a biomarker in diverse pathological contexts: it shows differential methylation in first-episode schizophrenia 3, altered expression in heart failure where it may involve cell cycle and lysosomal pathways 4, and association with interstitial cystitis through gut-microbiota interactions 5. These findings suggest PSME4 regulates both constitutive and stress-responsive proteasomal degradation pathways with implications across reproductive biology, cancer, and systemic diseases.