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HSP70: From molecular chaperone to integrative hub in castration-resistant prostate cancer therapeutic resistance

Qiuyu Liu1, Tianwen Huang2, Lu Li2

  • 1Guangxi Engineering Research Center for High-Value Utilization of Guangxi-Produced Authentic Medicinal Herbs, Institute of Traditional Chinese and Zhuang-Yao Ethnic Medicine, Guangxi University of Chinese Medicine, Nanning, 530200, China; Guangxi Key Laboratory of Marine Drugs, Institute of Marine Drugs, Guangxi University of Chinese Medicine, Nanning, 530200, China.

European Journal of Pharmacology
|June 29, 2026
PubMed

Insights

Heat shock protein 70 (HSP70) may coordinate resistance mechanisms in castration-resistant prostate cancer (CRPC). Targeting HSP70 interactions offers a new strategy to overcome treatment resistance in CRPC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Castration-resistant prostate cancer (CRPC) poses a significant therapeutic challenge, often driven by targets like androgen receptor splice variant 7 (AR-V7).
  • Current treatment strategies face limitations due to complex resistance mechanisms.
  • Heat shock protein 70 (HSP70) is increasingly recognized for its role in cellular stress response and protein homeostasis.

Purpose of the Study:

  • To propose a conceptual framework viewing heat shock protein 70 (HSP70) as a central hub coordinating multiple resistance mechanisms in CRPC.
  • To explore the hypothesis that HSP70 integrates pathways contributing to therapeutic resistance.
  • To identify potential therapeutic strategies targeting HSP70 to overcome CRPC resistance.

Main Methods:

  • Literature review and synthesis of existing evidence on HSP70 function in cancer.
  • Analysis of HSP70's association with key resistance pathways, including AR/AR-V7 stabilization, lineage plasticity (PLXND1), ferroptosis modulation (MBOAT2), and synthetic vulnerability (HSP60).
  • Conceptual modeling of HSP70 as an integrative resistance hub.

Main Results:

  • HSP70 is implicated in stabilizing oncoproteins like AR and AR-V7, crucial drivers of CRPC.
  • HSP70 may contribute to lineage plasticity via the Plexin D1 (PLXND1) pathway.
  • HSP70 is linked to ferroptosis modulation through the MBOAT2 axis and exhibits synthetic vulnerability with HSP60.

Conclusions:

  • HSP70 acts as a multidimensional hub coordinating diverse resistance mechanisms in CRPC.
  • Targeting specific HSP70 interactions and functions represents a promising precision medicine approach.
  • Leveraging HSP70 as a therapeutic target offers a framework to overcome CRPC resistance and improve patient outcomes.
Keywords:
Androgen receptorAndrogen receptor splicing variant 7Castration-resistant prostate cancerHeat shock protein 70Protein homeostasisTherapeutic resistance

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