HSP72

HSP72 (Heat Shock Protein 72) is a member of the heat shock protein family that serves as a bioactive signaling molecule, or exerkine, primarily released from the hepatosplanchnic circulation and skeletal muscle into the bloodstream in response to physical activity PMID 39136551PMID 39818278.

• Protein Homeostasis: HSP72 protects cells from metabolic stress by facilitating the proper folding of proteins and preventing the misfolding and aggregation of proteins PMID 39818278.
• Cellular Protection: It maintains cellular homeostasis and protects tissues from various forms of stress, including oxidative stress, mitochondrial dysfunction, and apoptosis PMID 39335489PMID 39852400.
• Metabolic Regulation: In skeletal muscle and adipose tissue, HSP72 improves glucose uptake by enhancing insulin signaling pathways, which is critical for maintaining systemic glucose homeostasis PMID 39818278.
• Inflammatory Modulation: It stimulates an anti-inflammatory heat shock response that promotes cell survival PMID 39818278.

• Exercise-Induced Secretion: HSP72 is classified as an exerkine because its levels are significantly induced by physical activity, particularly resistance exercise PMID 39818278PMID 39335489.
• Validated Human Release: Using sophisticated arterial-venous sampling techniques, researchers confirmed that HSP72 is released from the hepatosplanchnic circulation into the blood during acute exercise in humans PMID 39136551PMID 35304603.
• Multi-Organ Source: It is categorized as both an exercise-inducible hepatokine (from the liver) and a myokine (from skeletal muscle), acting through both autocrine and endocrine pathways PMID 39852400PMID 39335489.

• Type 2 Diabetes (T2DM): HSP72 has an ameliorative effect on T2DM, particularly in the elderly, by ensuring the integrity of pancreatic beta cells and promoting effective insulin secretion PMID 39818278. It is a potential therapeutic target for addressing insulin resistance PMID 39818278.
• Sarcopenia and Aging: It is identified as a promising therapeutic target for managing sarcopenia (age-related muscle loss) because it counteracts the oxidative stress and inflammation that drive the condition PMID 39852400.
• Oncology: HSP72 has been shown to bind to tumor cells, which improves the ability of immune cells to target and destroy them PMID 39136551.

Stress Response:

• It serves as a natural mediator of tissue repair and maintenance, helping to preserve functional capacity during the aging process PMID 39818278.

Cardiovascular protection represents a major therapeutic application. HSP72 administration has shown cardioprotective effects in ischemia-reperfusion injury through multiple mechanisms, including inhibition of apoptotic pathways (apoptosome, apoptosis-inducing factor, and nuclear factor-κB pathways) and facilitation of protein folding and chaperoning. PMID 28911512 A fusion construct (Fv-HSP72) combining HSP72 with a cell-penetrating antibody fragment has been validated in cerebral infarction models and is being tested clinically for ischemic events. PMID 27152638

Hepatoprotection has been demonstrated in transgenic mice overexpressing HSP72, which showed reduced liver injury from acetaminophen toxicity, methionine choline-deficient diet, and other hepatotoxic insults through attenuation of hepatocellular death, oxidative stress, and JNK signaling. PMID 29331340 HSP72 levels are elevated in patients with non-alcoholic steatohepatitis and chronic hepatitis C, correlating with hepatic inflammation severity. PMID 29331340

Neuroprotection occurs through inhibition of the JNK3 signaling pathway via Akt1 activation during cerebral ischemia, reducing neuronal death in hippocampal regions. PMID 22386689 HSP72 regulates both apoptotic and inflammatory signaling in cerebral ischemia, with net prosurvival effects. PMID 18648242

Anti-inflammatory effects involve inhibition of HMGB1 release and proinflammatory function in macrophages, interfering with the CRM1-dependent nuclear export pathway and suppressing MAP kinase and NF-κB pathways. PMID 17617616

Metabolic applications include potential therapeutic roles in obesity and type 2 diabetes, where HSP72 manipulation may improve glucose homeostasis by addressing inflammation, endoplasmic reticulum stress, and mitochondrial dysfunction. PMID 25379403

HSP72 has also been investigated for pulmonary cytoprotection as a medical countermeasure for inhalation toxicants and for maintaining protein homeostasis under heat stress through regulation of misfolded protein metabolism via autophagy pathways. PMID 27152638PMID 41306019

Human studies show more variable results compared to animal models, with some reporting protective effects while others suggest possible associations with mortality or infections in sepsis. PMID 24524071