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CAPRIN1-mediated sequestration of NCOA4 mRNA into stress granules drives sorafenib resistance in hepatocellular carcinoma

Oncogene (2026)Cite this article

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Abstract

Hepatocellular carcinoma (HCC) remains a leading cause of cancer-related mortality, with therapeutic resistance posing a critical barrier to improving patient outcomes. While stress granules (SGs) are implicated in tumor adaptation, their molecular features, clinical relevance, and mechanistic roles in HCC remain poorly defined. Here, we established a 26-gene SG signature and develop a SG score that robustly stratifies HCC patients, linking high score with aggressive molecular subtypes and poor survival. Moreover, we demonstrate that β-catenin directly binds the promoters of SG genes and activates their transcription. Crucially, we reveal that elevated SG activity correlates sorafenib resistance and identify CAPRIN1 as a key driver of sorafenib resistance through suppression of ferroptosis. Mechanistically, CAPRIN1 interacts with NCOA4 mRNA via its RGG domain and recruits NCOA4 mRNA into SGs, leading to repression of NCOA4 translation and consequent blunting of sorafenib-induced ferroptosis. Genetic disruption of CAPRIN1 restores NCOA4 expression and resensitizes resistant tumors to sorafenib. Our work establishes SG activity as a prognostic biomarker and reveals a druggable SG-ferroptosis axis, offering novel strategies to overcome therapy resistance in HCC.

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Fig. 1: SG score is upregulated and associated with worse prognosis in HCC.
Fig. 2: High SG activity is induced by β-catenin.
Fig. 3: High SG activity correlates with sorafenib resistance.
Fig. 4: CAPRIN1 confers resistance to sorafenib.
Fig. 5: CAPRIN1 suppresses sorafenib-induced ferroptosis.
Fig. 6: CAPRIN1 suppresses the translation of NCOA4.
Fig. 7: CAPRIN1 recruits NCOA4 mRNA into stress granules via direct interaction.
Fig. 8: Schematic diagram illustrates the mechanism of CAPRIN1 mediated sorafenib resistance in HCC cells.

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Data availability

Source data would been deposited in the Research Data Deposit (RDD) bank (http://www.researchdata.org.cn). All other data supporting the findings of this study are available from the corresponding author upon reasonable request.

References

  1. Rumgay H, Arnold M, Ferlay J, Lesi O, Cabasag CJ, Vignat J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022;77:1598–606.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.

    PubMed  Google Scholar 

  3. He X, Xu S, Tang L, Ling S, Wei X, Xu X. Insights into the history and tendency of liver transplantation for liver cancer: a bibliometric-based visual analysis. Int J Surg. 2024;110:406–18.

    Article  PubMed  PubMed Central  Google Scholar 

  4. European Association for the Study of the Liver. Electronic address eee, European Association for the Study of the L. EASL clinical practice guidelines: management of hepatocellular carcinoma. J Hepatol. 2018;69:182–236.

    Article  Google Scholar 

  5. Cancer Genome Atlas Research Network. Electronic address wbe, cancer genome atlas research N. Comprehensive and integrative genomic characterization of hepatocellular carcinoma. Cell. 2017;169:1327–41. e23.

    Article  Google Scholar 

  6. Schulze K, Imbeaud S, Letouze E, Alexandrov LB, Calderaro J, Rebouissou S, et al. Exome sequencing of hepatocellular carcinomas identifies new mutational signatures and potential therapeutic targets. Nat Genet. 2015;47:505–11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Villanueva A. Hepatocellular carcinoma. N Engl J Med. 2019;380:1450–62.

    Article  CAS  PubMed  Google Scholar 

  8. Cheng AL, Kang YK, Chen Z, Tsao CJ, Qin S, Kim JS, et al. Efficacy and safety of sorafenib in patients in the Asia-Pacific region with advanced hepatocellular carcinoma: a phase III randomised, double-blind, placebo-controlled trial. Lancet Oncol. 2009;10:25–34.

    Article  CAS  PubMed  Google Scholar 

  9. Huang C, Li Y, Zhang F, Zhang C, Ding Z. Advancements in elucidating the mechanisms of Sorafenib resistance in hepatocellular carcinoma. Int J Surg. 2025;111:2990–3005.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Raoul JL, Kudo M, Finn RS, Edeline J, Reig M, Galle PR. Systemic therapy for intermediate and advanced hepatocellular carcinoma: Sorafenib and beyond. Cancer Treat Rev. 2018;68:16–24.

    Article  CAS  PubMed  Google Scholar 

  11. Riggs CL, Kedersha N, Ivanov P, Anderson P. Mammalian stress granules and P bodies at a glance. J Cell Sci. 2020;133:jcs242487.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Glauninger H, Wong Hickernell CJ, Bard JAM, Drummond DA. Stressful steps: progress and challenges in understanding stress-induced mRNA condensation and accumulation in stress granules. Mol Cell. 2022;82:2544–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Millar SR, Huang JQ, Schreiber KJ, Tsai YC, Won J, Zhang J, et al. A new phase of networking: the molecular composition and regulatory dynamics of mammalian stress granules. Chem Rev. 2023;123:9036–64.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Lavalee M, Curdy N, Laurent C, Fournie JJ, Franchini DM. Cancer cell adaptability: turning ribonucleoprotein granules into targets. Trends Cancer. 2021;7:902–15.

    Article  CAS  PubMed  Google Scholar 

  15. Fonteneau G, Redding A, Hoag-Lee H, Sim ES, Heinrich S, Gaida MM, et al. Stress granules determine the development of obesity-associated pancreatic cancer. Cancer Discov. 2022;12:1984–2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Arimoto K, Fukuda H, Imajoh-Ohmi S, Saito H, Takekawa M. Formation of stress granules inhibits apoptosis by suppressing stress-responsive MAPK pathways. Nat Cell Biol. 2008;10:1324–32.

    Article  CAS  PubMed  Google Scholar 

  17. Grabocka E, Bar-Sagi D. Mutant KRAS enhances tumor cell fitness by upregulating stress granules. Cell. 2016;167:1803–13. e12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Thedieck K, Holzwarth B, Prentzell MT, Boehlke C, Klasener K, Ruf S, et al. Inhibition of mTORC1 by astrin and stress granules prevents apoptosis in cancer cells. Cell. 2013;154:859–74.

    Article  CAS  PubMed  Google Scholar 

  19. Adjibade P, St-Sauveur VG, Quevillon Huberdeau M, Fournier MJ, Savard A, Coudert L, et al. Sorafenib, a multikinase inhibitor, induces formation of stress granules in hepatocarcinoma cells. Oncotarget. 2015;6:43927–43.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Dolicka D, Foti M, Sobolewski C. The emerging role of stress granules in hepatocellular carcinoma. Int J Mol Sci. 2021;22:9428.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dolicka D, Zahoran S, Correia de Sousa M, Gjorgjieva M, Sempoux C, Fournier M, et al. TIA1 loss exacerbates fatty liver disease but exerts a dual role in hepatocarcinogenesis. Cancers (Basel). 2022;14:1704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Dixon SJ, Lemberg KM, Lamprecht MR, Skouta R, Zaitsev EM, Gleason CE, et al. Ferroptosis: an iron-dependent form of nonapoptotic cell death. Cell. 2012;149:1060–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Jiang X, Stockwell BR, Conrad M. Ferroptosis: mechanisms, biology and role in disease. Nat Rev Mol Cell Biol. 2021;22:266–82.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Stockwell BR, Jiang X, Gu W. Emerging mechanisms and disease relevance of ferroptosis. Trends Cell Biol. 2020;30:478–90.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Dixon SJ, Olzmann JA. The cell biology of ferroptosis. Nat Rev Mol Cell Biol. 2024;25:424–42.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Mishima E, Nakamura T, Doll S, Proneth B, Fedorova M, Pratt DA, et al. Recommendations for robust and reproducible research on ferroptosis. Nat Rev Mol Cell Biol. 2025;26:615–30.

    Article  CAS  PubMed  Google Scholar 

  27. Hassannia B, Vandenabeele P, Vanden Berghe T. Targeting ferroptosis to iron out cancer. Cancer Cell. 2019;35:830–49.

    Article  CAS  PubMed  Google Scholar 

  28. Nie J, Lin B, Zhou M, Wu L, Zheng T. Role of ferroptosis in hepatocellular carcinoma. J Cancer Res Clin Oncol. 2018;144:2329–37.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Galmiche A, Chauffert B, Barbare JC. New biological perspectives for the improvement of the efficacy of sorafenib in hepatocellular carcinoma. Cancer Lett. 2014;346:159–62.

    Article  CAS  PubMed  Google Scholar 

  30. Dixon SJ, Patel DN, Welsch M, Skouta R, Lee ED, Hayano M, et al. Pharmacological inhibition of cystine-glutamate exchange induces endoplasmic reticulum stress and ferroptosis. Elife. 2014;3:e02523.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Lachaier E, Louandre C, Godin C, Saidak Z, Baert M, Diouf M, et al. Sorafenib induces ferroptosis in human cancer cell lines originating from different solid tumors. Anticancer Res. 2014;34:6417–22.

    CAS  PubMed  Google Scholar 

  32. Louandre C, Ezzoukhry Z, Godin C, Barbare JC, Maziere JC, Chauffert B, et al. Iron-dependent cell death of hepatocellular carcinoma cells exposed to sorafenib. Int J Cancer. 2013;133:1732–42.

    Article  CAS  PubMed  Google Scholar 

  33. von Mering C, Huynen M, Jaeggi D, Schmidt S, Bork P, Snel B. STRING: a database of predicted functional associations between proteins. Nucleic Acids Res. 2003;31:258–61.

    Article  Google Scholar 

  34. Shannon P, Markiel A, Ozier O, Baliga NS, Wang JT, Ramage D, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003;13:2498–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Hanzelmann S, Castelo R, Guinney J. GSVA: gene set variation analysis for microarray and RNA-seq data. BMC Bioinforma. 2013;14:7.

    Article  Google Scholar 

  36. Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 2005;102:15545–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li L, Mao Y, Zhao L, Li L, Wu J, Zhao M, et al. p53 regulation of ammonia metabolism through urea cycle controls polyamine biosynthesis. Nature. 2019;567:253–6.

    Article  CAS  PubMed  Google Scholar 

  38. Jain S, Wheeler JR, Walters RW, Agrawal A, Barsic A, Parker R. ATPase-modulated stress granules contain a diverse proteome and substructure. Cell. 2016;164:487–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Markmiller S, Soltanieh S, Server KL, Mak R, Jin W, Fang MY, et al. Context-dependent and disease-specific diversity in protein interactions within stress granules. Cell. 2018;172:590–604. e13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Yang P, Mathieu C, Kolaitis RM, Zhang P, Messing J, Yurtsever U, et al. G3BP1 is a tunable switch that triggers phase separation to assemble stress granules. Cell. 2020;181:325–45. e28.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chandrashekar DS, Karthikeyan SK, Korla PK, Patel H, Shovon AR, Athar M, et al. UALCAN: An update to the integrated cancer data analysis platform. Neoplasia. 2022;25:18–27.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Lee JS, Chu IS, Heo J, Calvisi DF, Sun Z, Roskams T, et al. Classification and prediction of survival in hepatocellular carcinoma by gene expression profiling. Hepatology. 2004;40:667–76.

    Article  CAS  PubMed  Google Scholar 

  43. Hoshida Y, Nijman SM, Kobayashi M, Chan JA, Brunet JP, Chiang DY, et al. Integrative transcriptome analysis reveals common molecular subclasses of human hepatocellular carcinoma. Cancer Res. 2009;69:7385–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Boyault S, Rickman DS, de Reynies A, Balabaud C, Rebouissou S, Jeannot E, et al. Transcriptome classification of HCC is related to gene alterations and to new therapeutic targets. Hepatology. 2007;45:42–52.

    Article  CAS  PubMed  Google Scholar 

  45. Chiang DY, Villanueva A, Hoshida Y, Peix J, Newell P, Minguez B, et al. Focal gains of VEGFA and molecular classification of hepatocellular carcinoma. Cancer Res. 2008;68:6779–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Zhou N, Yuan X, Du Q, Zhang Z, Shi X, Bao J, et al. FerrDb V2: update of the manually curated database of ferroptosis regulators and ferroptosis-disease associations. Nucleic Acids Res. 2023;51:D571–D82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This project was supported by grants from the Guangzhou Science, Technology and Innovation Commission (2025A04J3972), the National Natural Science Foundation of China (82373092, 82372880), the Guangdong Basic and Applied Basic Research Foundation (2019A1515110140, 2023A1515030229), Guangzhou Key Medical Discipline Construction Project Fund (2025–2027), the NSFC Incubation Project of Guangdong Provincial People’s Hospital (KY0120220025), the High-level Hospital Construction Project of Guangdong Provincial People’s Hospital (KY012021197).

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Author notes

  1. These authors contributed equally: Mengyao Wang, Gengde Hong, Chengyue Zhang, Ying Xiao

Authors and Affiliations

  1. Radiation Oncology Department, Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong Province, People’s Republic of China

    Mengyao Wang, Chengyue Zhang, Ying Xiao, Falian Liang, Xizhen Jiang & Dongping Chen

  2. Department of Oncology and Hematology, The Sixth People’s Hospital of Huizhou City, Huiyang Hospital Affiliated to Southern Medical University, Huizhou, Guangdong Province, People’s Republic of China

    Gengde Hong

  3. Institute of Medical Research, Guangdong Provincial People’s Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, Guangdong Province, People’s Republic of China

    Zhirui Lin

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Contributions

Z-RL and D-PC conceptualized and supervised the research. M-YW, C-YZ, and YX contributed to the study design and performed most of the assays. G-DH and X-ZJ were engaged in biostatistics and bioinformatics analyses. M-YW and Z-RL prepared the manuscript. F-LL contributed to the analysis of clinical data. All authors discussed the results and approved of the final version.

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Correspondence to Mengyao Wang, Dongping Chen or Zhirui Lin.

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Wang, M., Hong, G., Zhang, C. et al. CAPRIN1-mediated sequestration of NCOA4 mRNA into stress granules drives sorafenib resistance in hepatocellular carcinoma. Oncogene (2026). https://doi.org/10.1038/s41388-026-03750-8

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