Heat shock factor 1 (HSF1) is a stress-protective transcription factor most associated with transcriptional regulation of genes involved thermal stress response and protein folding. The canonical activation cycle of HSF1, in which HSF1 recognizes a simple promoter binding site known as a heat shock element (HSE) to promote the transcription of molecular chaperones, has been well documented. However, it is now evident that mammalian HSF1 exhibits unexpected complexity and participates in the response to a vast array of cellular stress types. The versatility of HSF1 can be attributed to distinct local protein concentrations, posttranslational modifications (PTMs), and binding partners found in different anatomical regions of the mammalian system. Advances in our knowledge of HSF1 under different types of stress have illuminated its vast array of gene targets, ranging from protein folding to mitochondrial homeostasis to cytoskeletal stability and beyond. In this review, we explore current knowledge of mammalian HSF1 and its gene targets within the central nervous system. While HSF1 has been extensively studied in the context of neurodegeneration, our understanding of its diverse roles in this setting remains limited. We also highlight emerging evidence supporting a physiological role for HSF1 in the healthy brain, an area that has received relatively little attention. Advancing a more comprehensive understanding of HSF1 function in the mammalian brain may aid in the development of novel therapeutics aimed at alleviating symptoms across a range of neurological disorders.
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