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

作者：Jin Yan, Heyuan Liu, Wenguang Yang, Na Liu, Jingmei Wang, Zhanfeng Li, Tianya Liu, Siqi Yan, Wangxiao He · 发表于：Nature Communications · 年份：2025 · DOI：10.1038/s41467-025-61112-6 · 被引用次数：62 · 研究领域：Wnt/β-catenin signaling in development and cancer、RNA Research and Splicing、Caveolin-1 and cellular processes

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.