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

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.