<p>The cellular protein quality control and protein homeostasis is maintained by molecular chaperones that are upregulated in response to various environmental, chemical, thermal and genetic stress factors. Altered protein homeostasis owing to stress conditions lead to the accumulation of misfolded and aggregated protein conformers, a hallmark feature of several neurodegenerative and metabolic diseases. However, the effect of different stress conditions on the expression of molecular chaperones remains poorly understood. In the present study, comparative expression profile of the HSPA and DNAJ chaperone family has been analysed under oxidative stress induced by rotenone, proteotoxic stress induced by α-synuclein seeds, proteasome inhibitor and heat stress conditions. A dynamic and stress-selective expression of molecular chaperones was observed at both the gene and protein levels, where HSPA1 (HSP70), HSPA5 and DNAJB1 proteins were upregulated across all stress conditions, while HSPA8 (HSC70), HSPH1 (HSP110), DNAJB6 and DNAJB8 proteins exhibited stress-dependent unique expression patterns. The selective expression of molecular chaperones regulated through the NRF2/HSF1 axis suggests the involvement of the KEAP1/NRF2/ARE pathway in coordinating stress-dependent chaperone expression and ensuring proteome integrity. This comparative stress-specific expression profiling enables targeting of molecular chaperones to mitigate protein misfolding and aggregation, facilitating therapeutic interventions in neurodegenerative diseases.</p>