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RIOK1通过相分离形成应激颗粒限制PTEN翻译进而激活肝细胞癌肿瘤生长的机制研究

RIOK1 phase separation restricts PTEN translation via stress granules activating tumor growth in hepatocellular carcinoma

原文发布日期: 2025-06-04

英文摘要:

摘要翻译：

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RIOK1通过相分离形成应激颗粒限制PTEN翻译进而激活肝细胞癌肿瘤生长的机制研究

RIOK1 phase separation restricts PTEN translation via stress granules activating tumor growth in hepatocellular carcinoma

原文发布日期: 2025-06-04

英文摘要:

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.

摘要翻译：

对酪氨酸激酶抑制剂（TKIs）的耐药性限制了其在肝细胞癌（HCC）中的临床疗效。通过相分离形成的应激颗粒是应激反应的关键元件，并可介导治疗抵抗，但其在HCC中的作用机制尚不明确。本研究通过筛选发现非典型丝氨酸/苏氨酸激酶RIOK1在HCC中高表达，其表达水平与不良预后相关，且可在多种应激条件下被NRF2转录激活。RIOK1通过液-液相分离机制将IGF2BP1和G3BP1募集至应激颗粒，从而隔离PTEN信使RNA并抑制其翻译。该过程可激活磷酸戊糖途径，促进应激缓解并产生针对TKI的细胞保护作用。我们进一步证实小分子抑制剂西达本胺能下调RIOK1表达并增强TKI疗效。在HCC患者的多纳非尼耐药肿瘤组织中可检测到RIOK1阳性应激颗粒。这些发现揭示了应激颗粒动态变化、代谢重编程与HCC进展之间的关联，为提升TKI疗效提供了潜在干预策略。