硫酶响应相分离凝聚物向压力颗粒,以逆转肝细胞癌中索拉芬尼抗性的作用
Chenhui Wang1, Weishu Wang2, Yutong Li1
1Department of Cell Biology, School of Medicine, Nankai University, Tianjin, 300071, China.
Acta biomaterialia
|January 30, 2026
概括
研究人员开发了一种新型的联策略,以逆转肝细胞癌 (HCC) 中的索拉芬尼抗性. 这种方法通过诱导滴,增强亡和抑制瘤生长来准压力颗粒 (SGs).
科学领域:
- 生物化学 生物化学
- 分子生物学分子生物学
- 癌症研究 癌症研究
背景情况:
- 获得的耐药性,特别是肝细胞癌 (HCC) 中的索拉芬尼布耐药性 (SFR),显著限制了治疗结果.
- 由停滞的mRNA和像G3BPs这样的RNA结合蛋白形成的被称为压力颗粒 (SGs) 的无膜细胞器在SFR中发挥着至关重要的作用.
研究的目的:
- 开发一种使用刺激诱导的滴来抑制SG和逆转HCC中SFR的新型协体融合策略.
- 在HCC模型中研究这些联的作用机制和治疗疗效.
主要方法:
- 合成的硫酶反应性 (YsF和YsF-FGDF) 设计用于在遇到酸硫酶A (ARSA) 时进行液-液分离 (LLPS) 成为滴 (YsF-LSG).
- 在HCC-SFR细胞中通过克拉特林介导的内细胞分裂,溶酶体逃逸,以及YSF-LSG的现场LLPS进行了细胞吸收.
- 评估了SG的向性,G3BP2的招募,p38-Caspase-3信号的调节,以及诱导亡.
- 在HCC细胞衍生异种移植 (CDX) 模型中评估了YsF-LSG协同体与索拉芬尼结合的疗效.
主要成果:
- YsF-LSG混合物成功地在ARSA的反应中形成液滴,被HCC-SFR细胞内化,并在现场进行LLPS.
- 在现场形成的YsF-LSG协同有效地向SG,招募G3BP2,并通过缓解SG介导的亡抑制来逆转SFR.
- 在CDX模型中,YsF-LSG和sorafenib的组合疗法证明了增强抑制HCC-SFR生长和显著的抗瘤作用,具有良好的生物安全性.
结论:
- 这项研究提出了一种基于的新型同体策略,针对SG来克服HCC中的索拉芬尼布耐药性.
- YsF-LSG联为癌症治疗提供了一个有前途的方法,通过利用酶诱导的液体-液体相分离来逆转药物耐药性.
- 这项工作通过创新的生物材料设计为开发针对药物耐药癌症的向治疗提供了新的范式.
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