Impact of Two Small‐Molecule Proteasome Stimulators on Cellular Growth and Metabolism

The proteasome degrades ubiquitinated proteins as well as intrinsically disordered proteins that can be processed independently of ubiquitin signaling. The 20S core particle (CP) plays a key role in the degradation of unstructured proteins. Small molecules have been developed to enhance the degradation activity of the 20S CP; however, concerns remain that increasing 20S CP activity may promote cellular dysfunction or toxicity by altering cell proliferation or metabolic regulation. Here, we investigated the effects of two 20S CP stimulators on cell proliferation and on the expression of genes associated with growth and metabolism. Neither stimulator altered proliferation rates in any cell line examined nor did they significantly change growth‐associated gene expression in younger cell passages. In contrast, in older cell passages where overall proteasome activity is known to be altered, 20S CP stimulation resulted in measurable changes in gene expression without affecting proliferation. Together, these findings demonstrate that 20S CP stimulation does not inherently drive increased cell proliferation and challenge the prevailing assumption that enhanced 20S CP activity promotes uncontrolled cellular growth.