Protein misfolding and aggregation are widely implicated in an increasing number of human diseases providing
for new therapeutic opportunities targeting protein homeostasis (proteostasis). The cellular response to proteotoxicity is
highly regulated by stress signaling pathways, molecular chaperones, transport and clearance machineries that function as
a proteostasis network (PN) to protect the stability and functional properties of the proteome. Consequently, the PN is essential
at the cellular and organismal level for development and lifespan. However, when challenged during aging, stress,
and disease, the folding and clearance machineries can become compromised leading to both gain-of-function and loss-offunction
proteinopathies. Here, we assess the role of small molecules that activate the heat shock response, the unfolded
protein response, and clearance mechanisms to increase PN capacity and protect cellular proteostasis against proteotoxicity.
We propose that this strategy to enhance cell stress pathways and chaperone activity establishes a cytoprotective state
against misfolding and/or aggregation and represents a promising therapeutic avenue to prevent the cellular damage associated
with the variety of protein conformational diseases.