The Role of Hsp72 in Handing Misfolded Proteins Metabolism in Heat‐Stressed Cells: Mechanisms and Hypotheses

The accumulation of misfolded proteins within cells, often induced by stress, is a major contributor to cellular dysfunction. Heat shock proteins, which serve as critical chaperone molecules in response to stress‐related damage, are essential for maintaining protein homeostasis within cells. In this family of proteins, Heat Shock Protein 72 (Hsp72) stands out for its acute responsiveness to thermal stress. It can swiftly be produced in reaction to the surge of misfolded proteins caused by heat, thus maintaining the equilibrium of intracellular protein metabolism. This analysis explores the function of Hsp72 in maintaining protein homeostasis, focusing on its ability to assist in the refolding of incorrectly folded proteins and to guide their breakdown through the ubiquitin‐proteasome and autophagy systems. Furthermore, the potential mechanisms through which cells may eliminate misfolded protein aggregates via the secretory autophagy pathway under heat stress conditions are explored. This study systematically analyzes the various mechanisms by which Hsp72 influences misfolded protein metabolism and discusses the relevance of each pathway in the context of heat stress. Integrating findings from prior laboratory research, it is concluded that Hsp72 plays a pivotal role in regulating misfolded protein metabolism through the secretory autophagy pathway, thereby sustaining intracellular protein homeostasis during heat stress. This investigation expands the functional network of Hsp72 in maintaining protein homeostasis and elucidates the molecular pathways involved in its regulation of misfolded protein metabolism under heat stress, providing a framework for future research on Hsp72's role in cellular recovery from heat stress.