Progress in neuro-psychopharmacology & biological psychiatryJul 27, 2026

Targeting specific HSP90 protein types as a precise treatment approach for brain and metabolic diseases

Longevity & Aging Weekly Brief ↗PubMed ↗DOI ↗

Updated Jul 28, 2026

Abstract

Heat shock protein 90 (HSP90) is a central regulator of cellular proteostasis.

HSP90 consists of four paralogs: HSP90α, HSP90β, GRP94, and TRAP1, each with distinct roles in diseases.
In neurodegenerative disorders, abnormal HSP90 activity is linked to toxic protein accumulation, mitochondrial dysfunction, and chronic neuroinflammation.
Metabolic disorders show that signaling through GRP94 and TRAP1 can lead to endoplasmic reticulum stress and insulin resistance.
New HSP90 inhibitors are being developed to target specific paralogs, potentially allowing safer modulation of cellular processes.
Isoform-selective targeting of HSP90 may represent a promising therapeutic approach for conditions involving both neurodegeneration and metabolic dysfunction.

Simplified

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.

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No financial or personal ties reported.

PubMed

Targeting specific HSP90 protein types as a precise treatment approach for brain and metabolic diseases

Abstract

Full Text

Funding

Competing interests

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