The 19S proteasome as a therapeutic target in hematologic malignancies

The ubiquitin-proteasome system (UPS) is the primary intracellular pathway for maintaining protein homeostasis through the selective degradation of ubiquitinated proteins. Central to this process is the 26S proteasome, which orchestrates the turnover of regulatory and misfolded proteins and thereby controls critical cellular functions, including cell-cycle progression, apoptosis, DNA repair, signal transduction, and stress response pathways. Dysregulation of proteasome function contributes to many hallmarks of cancer, leading to malignant transformation, disease progression, and therapeutic resistance, making the proteasome an attractive target for anticancer therapy. Clinically approved proteasome inhibitors, including bortezomib, carfilzomib, and ixazomib, have significantly improved outcomes in multiple myeloma and other hematologic malignancies by targeting the catalytic activity of the 20S core particle. However, their long-term clinical benefit is limited by intrinsic and acquired resistance and treatment-related toxicities. Recent studies have identified the 19S regulatory particle as a mechanistically distinct and therapeutically promising target. Unlike the proteolytic 20S core, the 19S complex controls substrate recognition, deubiquitination, unfolding, and translocation into the proteolytic chamber. Beyond its role in protein degradation, the 19S regulatory particle participates in transcriptional regulation, chromatin remodeling, and DNA damage responses. Several 19S subunits, particularly members of the PSMD and PSMC families, are overexpressed in hematologic and solid malignancies and are associated with poor clinical outcomes. Genetic and pharmacologic targeting of 19S ATPases and deubiquitinating enzymes induces proteotoxic stress, overcomes resistance to conventional proteasome inhibitors, and suppresses tumor growth in preclinical models. In this review, we discuss the biological functions of the 19S regulatory particle, its role in cancer pathogenesis, and emerging therapeutic strategies targeting 19S-associated proteins to improve outcomes in hematologic malignancies.