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The Central Role and Therapeutic Potential of Cochaperone Networking of Chaperones in the Regulation of Biocondensates

  • Gregory L. Blatch 1,2,*,   
  • Adrienne L. Edkins 1,*

Received: 16 Nov 2025 | Revised: 20 Dec 2025 | Accepted: 23 Dec 2025 | Published: 01 Jan 2026

Abstract

Many heat shock proteins are essential molecular chaperones that safeguard proteome integrity (proteostasis) under both normal and stress conditions. These chaperones, especially heat shock protein 70 (Hsp70) and heat shock protein 90 (Hsp90), and their associated cochaperones, play central roles in cellular protein quality control (PQC) pathways, assisting in the folding of nascent polypeptides, refolding of stress-denatured proteins, and prevention of toxic aggregation. Dysregulation of this proteostasis network is implicated in numerous diseases, from neurodegenerative proteinopathies to cancer. Biocondensates are dynamic, membraneless phase-separated compartments that are emerging as major components of the PQC system. In this review, we discuss how the regulatory networking of chaperones by cochaperones, particularly J domain proteins (JDPs; also called Hsp40 or DNAJ proteins), contributes to biocondensate formation and protein disaggregation to maintain proteostasis. Furthermore, we highlight new mechanistic insights into phase separation and aggregate clearance with therapeutic potential. 

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Blatch, G. L.; Edkins, A. L. The Central Role and Therapeutic Potential of Cochaperone Networking of Chaperones in the Regulation of Biocondensates. Biomolecular Mechanisms and Innovations 2026, 1 (1), 3.
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