ArticleAdvanced science (Weinheim, Baden-Wurttemberg, Germany)2026
HSP70 Interactome-Mediated Proteolysis Targeting Chimera (HSP70-PROTAC) for Ferroptosis-Driven Cancer Treatment.
Article in Advanced science (Weinheim, Baden-Wurttemberg, Germany), 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 4 papers.
What it found
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Who cites it
4 citing papers in PubMed.
- A New Recruitable E3 Ligase UHRF1 Supporting Targeted Protein Degradation: A Minimal Azide as a Recruitment Ligand.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Curcumin Attenuates Decidual Stromal Cell Ferroptosis and Restores Impaired Decidualization in Recurrent Spontaneous Abortion by Targeting BRD4.Food science & nutrition · 2026Article
- GRP78 in human diseases: From molecular chaperone to therapeutic target.Theranostics · 2026Review
- Protein Post-Translational Modifications in the Regulation of Ferroptosis: New Opportunities and Challenges for Cancer Immunotherapy.International journal of biological sciences · 2026Review
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Authors and funding
16 authors.
Funding
Abstract
Targeted protein degradation (TPD) represents a transformative therapeutic paradigm that harnesses the cellular degradation machinery to pharmacologically eliminate disease-causing proteins with aberrant expression. This work here reports the first design of an HSP70 interactome-mediated proteolysis targeting chimera (HSP70-PROTAC) for the degradation of the intracellular therapeutically relevant proteins via dual processes of ubiquitin-proteasomal degradation (UPS) and chaperone-mediated autophagy (CMA). By hijacking the highly expressed heat shock cognate protein (Hsc70) isoform complex in tumor tissues to glutathione peroxidase 4 (GPX4) protein, this work successfully develops an HSP70-PROTAC molecule GDAz-3 that potently and rapidly eliminates GPX4 in HT1080 cells, thereby triggering ferroptosis with high selectivity. Correspondingly, GDAz-3 exhibits a remarkable tumor-inhibitory effect in the HT1080 xenograft tumor mouse model without obvious toxicity. In addition, this work demonstrates the versatility of HSP70-based PROTACs by effectively degrading additional endogenous bromodomain-containing protein 4 (BRD4) in cancer cells. More importantly, the degradation of GPX4 mediated by GDAz-3 occurs with comparable efficiency in CRBN/VHL-knockdown cells and 786-O cells intrinsically lacking VHL expression, which facilitates expanding the application scope and overcoming drug resistance of traditional PROTAC. These findings suggest that HSP70-PROTAC is a novel and feasible strategy for the future development of TPD technology.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.