Stimulating proteasomal degradation in human proteinopathies

The ubiquitin-proteasome system (UPS) comprises hundreds of proteins that orchestrate ubiquitin-dependent proteasomal degradation and represents a powerful therapeutic target for modulating intracellular protein turnover. Due to its central role in preventing the accumulation of misfolded and dysfunctional proteins, enhancing or suppressing UPS activity offers clinical potential across a wide spectrum of diseases. While oncology has successfully capitalized on this vulnerability through the development of proteasome inhibitors for the treatment of hematological malignancies, efforts to generate clinically relevant UPS activators have progressed more slowly. Bridging this therapeutic gap could be particularly beneficial for neurodegenerative diseases and other proteinopathies, where accelerating the removal of misfolded and aggregation-prone proteins may help counteract their progressive accumulation and delay, or prevent the onset of symptoms. In this review, we summarize the progress made so far toward finding strategies to boost UPS function through genetic or small-molecule interventions.