Heat shock response pathway (HSR)

The Heat shock response (HSR) pathway is a fundamental cellular mechanism dedicated to maintaining protein homeostasis (proteostasis) under conditions of proteotoxic stress, such as elevated temperature, oxidative damage, or heavy metal exposure [3, 4]. It is primarily orchestrated by the transcription factor Heat Shock Factor 1 (HSF1), which, upon activation, induces the rapid synthesis of molecular chaperones known as heat shock proteins (HSPs), including HSP70, HSP90, and small HSPs [7, 10]. These chaperones facilitate the refolding of denatured proteins, prevent cytotoxic aggregation, and target irreversibly damaged proteins for degradation via the ubiquitin-proteasome system [1, 5]. In the context of oncology, many tumors overexpress components of the HSR to stabilize mutated or overexpressed oncoproteins (client proteins) and evade apoptosis, leading to the development of HSP90 and HSF1 inhibitors as potential anti-cancer agents [2, 8]. Conversely, in neurodegenerative diseases like Alzheimer's and Parkinson's, where protein aggregation is a hallmark, pharmacological induction of the HSR is being investigated to enhance the cell's natural defense against misfolded proteins [2, 4].

Other names

Proteotoxic stress responseHeat shock response

Modulation of the heat shock response typically involves either the inhibition of molecular chaperones like HSP90 to promote the degradation of oncogenic client proteins or the induction of the pathway to enhance the refolding of misfolded proteins in neurodegenerative contexts [1, 4, 8].