Heat Shock Proteins in Schizophrenia: Integrating Stress Responses, Molecular Pathways, and Emerging Therapeutic...

Schizophrenia is a severe mental disorder characterized by a range of symptoms and significant disability, with disrupted proteostasis identified as a critical pathophysiological factor. This comprehensive review evaluates the involvement of heat shock proteins (HSPs) in schizophrenia, highlighting immunologic, genetic, and expression-based evidence, while proposing a potential role for cold shock proteins (CSPs). HSPs, particularly HSP60, HSP70, and HSP90, function as molecular chaperones essential for maintaining proteostasis during stress. HSP autoantibodies are increased in individuals with schizophrenia, and levels correlate with symptom severity, blood-brain barrier dysfunction, and response to antipsychotics such as clozapine. Genetic research links HSP gene polymorphisms (e.g., HSPA1A, HSPA1B, and HSPB1) to disease risk, symptom severity, and treatment outcomes. Altered HSP levels in brain regions like the dorsolateral prefrontal cortex suggest roles in neuroprotection, oxidative stress, and synaptic dysfunction. Antipsychotics modulate HSP expression, indicating potential for precision medicine using HSP coinducers like BGP-15. While HSPs are well linked to schizophrenia, limited evidence suggests that CSPs could affect deficits in synaptic structure and pruning, known to play a role in schizophrenia, through actions involving BDNF-TrkB signaling. Despite recent advancements, challenges remain in achieving consistent immune responses, ensuring genetic relevance across populations, and fully understanding the importance of CSPs, which calls for longitudinal multiomics studies, diverse cohort analyses, and advanced preclinical models. This review positions HSPs as central to the molecular framework of schizophrenia and CSPs as a largely unexplored area, advocating for integrated research to enhance mechanistic understanding and therapeutic approaches for this complex disorder.