Small-molecule-induced liquid-liquid phase separation suppresses the carcinogenesis of β-catenin

Jin Yan, Heyuan Liu, Wenguang Yang, Na Liu, Jingmei Wang, Zhanfeng Li, Tianya Liu, Siqi Yan and Wangxiao He ()
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Jin Yan: The First Affiliated Hospital of Xi’an Jiaotong University
Heyuan Liu: The Second Affiliated Hospital of Xi’an Jiaotong University
Wenguang Yang: The First Affiliated Hospital of Xi’an Jiaotong University
Na Liu: The First Affiliated Hospital of Xi’an Jiaotong University
Jingmei Wang: The Second Affiliated Hospital of Xi’an Jiaotong University
Zhanfeng Li: The First Affiliated Hospital of Xi’an Jiaotong University
Tianya Liu: The Second Affiliated Hospital of Xi’an Jiaotong University
Siqi Yan: The Second Affiliated Hospital of Xi’an Jiaotong University
Wangxiao He: The First Affiliated Hospital of Xi’an Jiaotong University

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract Biomolecular condensates are droplet-like membrane-less compartments in cells that can sequester proteins. Modulating these condensates offers a promising way to durably inhibit disease-driving proteins that lack enzymatic activity and thus elude traditional drug targeting. However, many such proteins remain beyond the reach of current condensate-modulating strategies. Here we show an alternative approach: by destabilizing target proteins, we directly induce their liquid–liquid phase separation (LLPS), causing them to form condensates. Using this strategy, we develop a small molecule RQ that forces β-catenin (an oncogenic protein in liver cancer) into cytoplasmic condensates. This sequestration prevents β-catenin from entering the nucleus and activating cancer-promoting genes. In nanoparticle form (albumin-bound Abroquinone), RQ is selectively taken up by β-catenin-driven liver cancer cells and kills them while sparing normal cells. This approach suppresses β-catenin-driven tumor growth and overcomes immune evasion, demonstrating a promising paradigm for targeting previously untargetable proteins by inducing their phase separation.

Date: 2025
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DOI: 10.1038/s41467-025-61112-6

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