Isoform-selective HSP90 inhibition as a precision therapeutic strategy for neurodegenerative and metabolic diseases.
Isoform-selective HSP90 inhibition as a precision therapeutic strategy for neurodegenerative and metabolic diseases.
Where did the research take place?
The study site has not been established. Author addresses may differ from where the research occurred.
Arar, SA · Author affiliation
Department of Medical Laboratory Technology, College of Applied Medical Science, Northern Border University, Arar, Saudi Arabia. Electronic address: Sultan.alanazi2@nbu.edu.sa.Location evidence
Baghdad, IQ · Author affiliation
Department of Clinical Pharmacology and Medicine, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq. Electronic address: haydermutter@uomustansiriyah.edu.iq.Location evidence
Vienna, AT · Author affiliation
European Academy of Sciences and Arts, Vienna, Austria; University Centre for Research & Development, Chandigarh University, Chandigarh-Ludhiana Highway, Mohali, Punjab, India.Location evidence
Chandigarh, IN · Author affiliation
European Academy of Sciences and Arts, Vienna, Austria; University Centre for Research & Development, Chandigarh University, Chandigarh-Ludhiana Highway, Mohali, Punjab, India.Location evidence
Mohali, IN · Author affiliation
European Academy of Sciences and Arts, Vienna, Austria; University Centre for Research & Development, Chandigarh University, Chandigarh-Ludhiana Highway, Mohali, Punjab, India.Location evidence
Ioánnina, GR · Author affiliation
Faculty of Medicine, Health Sciences School, University of Ioannina, University Campus, 45110 Ioannina, Greece. Electronic address: marios_papadakis@uoi.gr.Location evidence
Cairo, EG · Author affiliation
Department of Pharmacology and Toxicology, Faculty of Pharmacy, Egyptian Russian University, Badr City, Cairo-Suez Road, 11829 Cairo, Egypt. Electronic address: safaa-faheem@eru.edu.eg.Location evidence
Damanhur, EG · Author affiliation
Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhur University, Damanhur 22511, AlBeheira, Egypt. Electronic address: Gaberelsaberbatiha@gmail.com.Location evidence
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Original abstract
Heat shock protein 90 (HSP90) is a central regulator of cellular proteostasis, coordinating the folding, stabilization, and turnover of a wide range of client proteins in the cytosol, endoplasmic reticulum, and mitochondria. Accumulating evidence indicates that the four HSP90 paralogs HSP90α, HSP90β, GRP94, and TRAP1 have distinct pathological roles in neurodegenerative and metabolic diseases. In neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, Huntington's disease, and amyotrophic lateral sclerosis, aberrant HSP90 activity contributes to the persistence of toxic protein conformers, defective autophagy, mitochondrial dysfunction, and chronic neuroinflammation. In metabolic disorders such as obesity, type 2 diabetes, and metabolic dysfunction-associated steatotic liver disease, GRP94- and TRAP1-dependent signaling promotes endoplasmic reticulum stress, impaired mitochondrial metabolism, insulin resistance, and inflammatory remodeling. These mechanistic insights have accelerated the development of a new generation of HSP90 inhibitors with improved selectivity, tissue targeting, and brain penetration. Unlike earlier pan-HSP90 inhibitors, these compounds are designed to exploit paralog-specific vulnerabilities and may enable safer long-term modulation of disease-relevant chaperone networks. This review summarizes current advances in the biology and pharmacology of HSP90 paralogs and proposes isoform-selective HSP90 targeting as a promising therapeutic strategy at the intersection of neurodegeneration and metabolic dysfunction.