Heat shock transcription factors in development and disease

The heat shock response is a highly conserved cellular defense mechanism against proteotoxic stress, characterized by the induction of heat shock proteins (HSPs) that function as molecular chaperones to maintain protein homeostasis. Central to this response are the heat shock transcription factors (HSFs), which regulate the expression of HSPs. This Review explores the structural and functional relationships of the mammalian HSF family, including HSF1, HSF2, HSF4 and HSF5. We highlight HSF gene expression and function during organismal development and details of HSFs involvement in neurodegenerative diseases, in which they mitigate/counteract protein aggregation and promote neuronal survival, and in cancer, in which they support tumor growth and metastasis. We also examine the interplay between different HSFs and their context-dependent functions, emphasizing their relevance as potential targets for therapeutic intervention. Understanding the diverse roles of these factors is essential for advancing our knowledge of physiological regulation, and for developing targeted therapies for a broad range of diseases.