Abstract Background Osteoporosis is a systemic bone disorder marked by reduced bone mass and deteriorating bone microstructure, commonly associated with inflammation, oxidative stress, and imbalances in immune homeostasis. Among the key mechanisms underlying Osteoporosis progression, disruption of the bone immune microenvironment has emerged as a critical scientific issue. Heat shock proteins (HSPs), as highly conserved molecular chaperones and stress-responsive proteins, not only prevent protein misfolding and aggregation under stress conditions to maintain protein homeostasis, but also participate in immune signaling and adaptive stress responses, thereby playing important roles in preserving bone metabolic homeostasis. Main body of the abstract This review aims to systematically examine the roles of HSP families—HSPB, HSP40, HSP70, HSP90, and HSP110—in bone remodeling, the balance between osteogenesis and osteoclastogenesis, and the interaction between endoplasmic reticulum stress and mitochondrial energy metabolism. The review also highlights the dual roles of HSPs in regulating bone immune homeostasis. HSPs participate at the cellular level in regulating osteoblast, osteoclast, and bone marrow mesenchymal stem cell function. Current evidence suggests that HSPs act as both molecular chaperones and stress-responsive immune modulators, regulating the balance between bone formation and bone resorption and remodeling the bone immune microenvironment. This review also summarizes HSP-targeted therapeutic strategies, including small molecules, natural products, neutralizing antibodies, physical stimulation, and gene- and cell-based therapies. Conclusion Research on HSPs is shifting from molecular mechanisms toward precision intervention. Future studies should integrate the “bone-muscle-immune axis” with artificial intelligence and multi-omics technologies to construct a “heat shock response-bone immune” network, identify novel therapeutic targets, and promote personalized prevention and treatment of osteoporosis.
An et al. (Mon,) studied this question.