Pharmacological and genetic modulation of heat shock proteins: current approaches and therapeutic perspectives

Molecular chaperones, or heat shock proteins (HSPs), constitute a highly conserved class of proteins responsible for the correct folding of polypeptides and the prevention of their misfolding and aggregation, thereby maintaining cellular proteostasis. These proteins are classified into several families based on molecular weight — including HSP40, HSP60, HSP70, HSP90, HSP110, and small HSPs — and act in coordination with co-chaperones as central components of the cellular protein quality control system. Chaperones participate in numerous cellular processes, including the folding of newly synthesized proteins, refolding of denatured or unstable proteins, assembly of protein complexes, disaggregation, and degradation of defective polypeptides.
Through these mechanisms, HSPs protect cells from stress (e.g., heat shock) and support protein homeostasis; activation of the chaperone response is regulated by heat shock transcription factors (HSFs) in response to stress stimuli.
Dysfunction or imbalance in chaperone activity is associated with a range of pathologies: in neurodegenerative diseases, the accumulation of toxic protein aggregates (such as amyloid-beta and tau in Alzheimer’s disease) is counteracted by HSP activity, whereas in cancer, the overexpression of HSPs contributes to tumor cell survival and malignant progression. Given their pivotal role, molecular chaperones are actively investigated as targets for therapeutic modulation. Pharmacological inhibitors of HSP90 are currently undergoing clinical trials as anticancer agents, while HSF1/chaperone inducers and gene therapy strategies are being explored to enhance proteostasis in proteinopathies. Promising directions also include vaccines based on HSP–antigen complexes, which utilize chaperones as adjuvants to stimulate immune responses, as well as proteostasis-oriented therapies aimed at restoring protein homeostasis within the cell.

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