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Numerous extrinsic and intrinsic insults trigger the  HSF 1‐mediated proteotoxic stress response ( PSR ), an ancient transcriptional program that is essential to proteostasis and survival under such conditions. In contrast to its well‐recognized mobilization by proteotoxic stress, little is known about how this powerful adaptive mechanism reacts to other stresses. Surprisingly, we discovered that metabolic stress suppresses the  PSR . This suppression is largely mediated through the central metabolic sensor  AMPK , which physically interacts with and phosphorylates  HSF 1 at Ser121. Through  AMPK  activation, metabolic stress represses  HSF 1, rendering cells vulnerable to proteotoxic stress. Conversely, proteotoxic stress inactivates  AMPK  and thereby interferes with the metabolic stress response. Importantly, metformin, a metabolic stressor and popular anti‐diabetic drug, inactivates  HSF 1 and provokes proteotoxic stress within tumor cells, thereby impeding tumor growth. Thus, these findings uncover a novel interplay between the metabolic stress sensor  AMPK  and the proteotoxic stress sensor  HSF 1 that profoundly impacts stress resistance, proteostasis, and malignant growth.

Suppression of the HSF 1‐mediated proteotoxic stress response by the metabolic stress sensor AMPK