Meng Fanzheng, Li Hairui, Huang Yabin, Wang Chunxu, Liu Yufeng, Zhang Chunting, Chen Danlei, Zeng Taofei, Zhang Shenyu, Li Yunyun, Zhang Bo, Lang Chuandong, Xia Jie, Xiong Wanxiang, Pan Shixiang, Sun Xuedan, Thorne Rick F, Liu Yao, Wang Jiabei, Zhang Shugeng, Song Ruipeng, Wang Jizhou, Liu Lianxin
Department of Hepatobiliary Surgery, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
Anhui Provincial Key Laboratory of Hepatopancreatobiliary Surgery, Hefei, China.
Nat Cancer. 2025 Jun 4. doi: 10.1038/s43018-025-00984-5.
Resistance to tyrosine kinase inhibitors (TKIs) dampens their clinical efficacy in hepatocellular carcinoma (HCC). Stress granules formed by phase separation are essential to stress response and can be involved in therapy resistance, but their mechanisms in HCC are unclear. Here our screen shows that the atypical serine/threonine kinase RIOK1 is highly expressed in HCC, linked to poor prognosis, and transcriptionally activated by NRF2 under various stress conditions. RIOK1 undergoes liquid-liquid phase separation by incorporating IGF2BP1 and G3BP1 into stress granules that sequestrate PTEN messenger RNA reducing its translation. This process activates the pentose phosphate pathway, facilitating stress resolution and cytoprotection against TKI. We further show that the small-molecule inhibitor chidamide downregulates RIOK1 and enhances TKI efficacy. RIOK1-positive stress granules are found in donafenib-resistant tumors from patients with HCC. These findings reveal a link between stress granule dynamics, metabolic reprogramming and HCC progression, offering the potential means to improve TKI efficacy.
对酪氨酸激酶抑制剂（TKIs）的耐药性削弱了它们在肝细胞癌（HCC）中的临床疗效。由相分离形成的应激颗粒对于应激反应至关重要，并且可能参与治疗耐药性，但其在HCC中的机制尚不清楚。在这里，我们的筛选显示非典型丝氨酸/苏氨酸激酶RIOK1在HCC中高表达，与不良预后相关，并且在各种应激条件下被NRF2转录激活。RIOK1通过将IGF2BP1和G3BP1纳入应激颗粒进行液-液相分离，这些应激颗粒隔离PTEN信使核糖核酸从而减少其翻译。这一过程激活磷酸戊糖途径，促进应激解决和对TKI的细胞保护。我们进一步表明，小分子抑制剂西达本胺下调RIOK1并增强TKI疗效。在HCC患者的多纳非尼耐药肿瘤中发现了RIOK1阳性应激颗粒。这些发现揭示了应激颗粒动态、代谢重编程与HCC进展之间的联系，为提高TKI疗效提供了潜在手段。
