Authors
Si-Han Zhang, Ye An, Na Zeng, Mei-Cheng Liu, Jian-Xuan Sun, Xi Gong, Jin-Zhou Xu, Shao-Gang Wang, Qi-Dong Xia
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Pages e77932. Sep 27, 2026. Epub Sep 27, 2026.
Abstract
Glutathione peroxidase 4 (GPX4) is a central guardian against ferroptosis and a critical therapeutic target for castration-resistant prostate cancer (CRPC). However, traditional GPX4 inhibitors are often limited by irreversible covalent binding and systemic toxicity. Here, we utilized the deep learning algorithm Bindcraft to design high-affinity de novo binders targeting GPX4. To achieve GPX4 degradation, we developed a novel modality termed binder-degron chimera (bdC), which integrates a de novo-designed binder with a C-terminal combinational degron. Mechanistically, bdC recruits the CUL2-RING E3 ubiquitin ligase complex, leading to proteasome-mediated GPX4 degradation. To circumvent the delivery barriers inherent to macromolecular therapeutics, the bdC was encoded into a plasmid vector and encapsulated within a biomimetic nanocarrier featuring a PSMA-targeted and CD47-camouflaged surface (pc-CMNP). This platform enables the in situ synthesis of bdCs specifically within prostate cancer cells, driving robust GPX4 degradation and triggering potent ferroptosis. Our work establishes a versatile framework combining deep-learning generative binders, combinational degrons, and biomimetic nanotechnology to degrade intracellular targets and provides a novel therapeutic modality for CRPC.
PMID:
42801636
Bibliographic data and abstract were imported from PubMed on 28 Sep 2026.
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