RIOK1 phase separation restricts PTEN translation via stress granules activating tumor growth in hepatocellular carcinoma
Abstract
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.
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LLPS plays key roles in fundamental biological processes such as cytoskeletal regulation, synaptic signaling, and stress granule formation.
“In addition, LLPS plays key roles in fundamental biological processes such as cytoskeletal regulation, 26 synaptic signaling, 49 and stress granule formation. 50 , 51”
From Aberrant phase separation from a rare <i>ABI3</i> mutation drives microglial dysfunction and Alzheimer's risk (2026) · cites this paper as [50]
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Sun, X., Ou, Z., Chen, R., Niu, X., Chen, D., Kang, R., & Tang, D. (2016) · Hepatology · doi:10.1002/hep.28251 · Cited by 2,012 · see citing works
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Li, S., Lu, J., Zeng, K., Lu, X., Zhang, J., Feng, S., Liang, C., Cai, Y., Yao, S., Huang, Q., et al. (2026) · Alzheimer's & Dementia · doi:10.1002/alz.71812
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- Authors
- Meng, F., Li, H., Huang, Y., Wang, C., Liu, Y., Zhang, C., Chen, D., Zeng, T., Zhang, S., Li, Y., Zhang, B., Lang, C., Xia, J., Xiong, W., Pan, S., Sun, X., Thorne, R. F., Liu, Y., Wang, J., Zhang, S., Song, R., Wang, J., & Liu, L.
- Affiliations
- University of Science and Technology of China (CN)
- Henan Provincial People's Hospital (CN)
- Corresponding author
- Zhang, Shenyu
- Wang, Jiabei
- Zhang, Shugeng
- Song, Ruipeng
- Wang, Jizhou
- Liu, Lianxin
- ORCID
- Venue
- Nature Cancer
- Published
- 2025-06-04
- Volume
- 6
- Issue
- 7
- Pages
- 1223-1241
- ISSN
- 2662-1347 (ISSN-L)
- OpenAlex
- W4411036756
- Cited by
- 31
- References
- 1
- Citations by year
- 2026: 22 · 2025: 9
- FWCI
- 8.56
- Type
- journal article
- Language
- en
- Update notices
- correction (2025-08-04)
- Open access
- closed
- Licence
- Locations
- Nature Cancer (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Natural Science Foundation of China (U19A2008、81972307, 82103219, 82101480, 82272787, 82272700, 82170618)
- National Key R&D Program of China
- Natural Science Foundation of Anhui Province (2108085QH343, 2108085QH325, 2208085J47, 2208085MH245, 2108085MH288)
- Postdoctoral Research Foundation of China (2022T150623,2020M682023, 2021TQ0324)
- University of Science and Technology of China (WK9110000153, WK9110000164, YD9110002048, YD9100002003)
- Chinese Society of Clinical Oncology (Y-JS2019-014)
- Anhui Department of Education (2022AH020077)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Research and Splicing
- Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › PI3K/AKT/mTOR signaling in cancer
- Keywords
- RIOK1, liquid-liquid phase separation, stress granules, hepatocellular carcinoma, tyrosine kinase inhibitor resistance, Nrf2, IGF2BP1, G3BP1, pentose phosphate pathway, metabolic reprogramming, chidamide, donafenib, mRNA sequestration
- MeSH terms
- RNA Recognition Motif Proteins, Poly-ADP-Ribose Binding Proteins, Stress Granules, Phase Separation, Animals, Benzamides, Benzylamines, DNA Helicases, Carcinoma, Hepatocellular, Humans, Liver Neoplasms, Protein Biosynthesis, Gene Expression Regulation, Neoplastic, RNA-Binding Proteins, Protein Serine-Threonine Kinases, Drug Resistance, Neoplasm, RNA Helicases, Cell Line, Tumor, Protein Kinase Inhibitors, Cell Proliferation, PTEN Phosphohydrolase, NF-E2-Related Factor 2, Mice
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