Targeting the ERO1A–PDIA1 redox axis in triple-negative breast cancer with AI-designed minibinders
- 1Istituto di Ricerche Farmacologiche Mario Negri IRCCS
- 2U.O. Patologia Mammaria e Tumori Cerebrali, Azienda Socio-Sanitaria Territoriale
- 3Division of Hematology, Department of Medicine and Department of Pathology and Immunology, Washington University School of Medicine
Abstract
Endoplasmic reticulum oxidoreductin 1 alpha (ERO1A), together with its partner protein disulfide isomerase A1 (PDIA1), promotes oxidative protein folding within the endoplasmic reticulum (ER), thereby supporting ER redox homeostasis, proteostasis, and cancer progression. Importantly, ERO1A enhances the aggressiveness and therapy resistance of triple-negative breast cancer (TNBC), while PDIA1 is also upregulated and positively correlates with ERO1A expression in TNBC. These observations suggest that targeting the ERO1A–PDIA1 interaction may simultaneously impair the activity of both proteins, thereby providing a dual-hit anti-cancer strategy. Guided by AI-based structural modeling of the ERO1A–PDIA1 interface, we used the BindCraft pipeline to design and rank one hundred de novo protein minibinders targeting the b′ domain of PDIA1, from which eight top-scoring, non-redundant candidates were selected for experimental characterization. In vitro biochemical assays using recombinant proteins demonstrated direct binding of three minibinders (mb) to PDIA1 and inhibition of both the ERO1A–PDIA1 electron transfer relay and the intrinsic reductase activity of PDIA1. Furthermore, liposome-mediated intracellular delivery of mb7 impaired TNBC cell viability, providing proof-of-concept evidence that the minibinder can restrain tumor cell survival. Overall, our work provides a rationale for the development of highly specific and stable protein-based modulators of the ERO1A–PDIA1 interaction, which, by simultaneously inhibiting the activities of both ERO1A and PDIA1, may represent an effective strategy to restrain TNBC progression and counteract therapy resistance.
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BibTeX
@article{marrazza2026targeting,
title = {{Targeting the ERO1A–PDIA1 redox axis in triple-negative breast cancer with AI-designed minibinders}},
author = {Alice Marrazza and Sara Baroni and Ersilia Varone and Alessandro Cherubini and Serena Germani and Giorgia Maria Renna and Daniele Generali and Manuela Milani and Mirko Marabese and Monica Favagrossa and Alessia Porta and Giorgia Giordano and Alfredo Cagnotto and Luca Guarrera and Marco Gobbi and Bo-Ram Jin and Jaehyung Cho and Marten Beeg and Ester Zito},
journal = {Cell Death Discovery},
year = {2026},
month = aug,
doi = {10.1038/s41420-026-03301-w},
url = {https://doi.org/10.1038/s41420-026-03301-w},
note = {CC BY},
}
RIS
TY - JOUR
TI - Targeting the ERO1A–PDIA1 redox axis in triple-negative breast cancer with AI-designed minibinders
AU - Alice Marrazza
AU - Sara Baroni
AU - Ersilia Varone
AU - Alessandro Cherubini
AU - Serena Germani
AU - Giorgia Maria Renna
AU - Daniele Generali
AU - Manuela Milani
AU - Mirko Marabese
AU - Monica Favagrossa
AU - Alessia Porta
AU - Giorgia Giordano
AU - Alfredo Cagnotto
AU - Luca Guarrera
AU - Marco Gobbi
AU - Bo-Ram Jin
AU - Jaehyung Cho
AU - Marten Beeg
AU - Ester Zito
PY - 2026
DA - 2026/08/01
JO - Cell Death Discovery
DO - 10.1038/s41420-026-03301-w
UR - https://doi.org/10.1038/s41420-026-03301-w
AB - Endoplasmic reticulum oxidoreductin 1 alpha (ERO1A), together with its partner protein disulfide isomerase A1 (PDIA1), promotes oxidative protein folding within the endoplasmic reticulum (ER), thereby supporting ER redox homeostasis, proteostasis, and cancer progression. Importantly, ERO1A enhances the aggressiveness and therapy resistance of triple-negative breast cancer (TNBC), while PDIA1 is also upregulated and positively correlates with ERO1A expression in TNBC. These observations suggest that targeting the ERO1A–PDIA1 interaction may simultaneously impair the activity of both proteins, thereby providing a dual-hit anti-cancer strategy. Guided by AI-based structural modeling of the ERO1A–PDIA1 interface, we used the BindCraft pipeline to design and rank one hundred de novo protein minibinders targeting the b′ domain of PDIA1, from which eight top-scoring, non-redundant candidates were selected for experimental characterization. In vitro biochemical assays using recombinant proteins demonstrated direct binding of three minibinders (mb) to PDIA1 and inhibition of both the ERO1A–PDIA1 electron transfer relay and the intrinsic reductase activity of PDIA1. Furthermore, liposome-mediated intracellular delivery of mb7 impaired TNBC cell viability, providing proof-of-concept evidence that the minibinder can restrain tumor cell survival. Overall, our work provides a rationale for the development of highly specific and stable protein-based modulators of the ERO1A–PDIA1 interaction, which, by simultaneously inhibiting the activities of both ERO1A and PDIA1, may represent an effective strategy to restrain TNBC progression and counteract therapy resistance.
SN - 2058-7716
ER -