Hidden Proteomes: A Systematic Review of Translatable circRNAs in Oncology
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Hidden Proteomes: A Systematic Review of Translatable circRNAs in Oncology

Yijia Zhu 1*
1 University of California
*Corresponding author: yjizhu@ucdavis.edu
Published on 26 November 2025
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TNS Vol.152
ISSN (Print): 2753-8826
ISSN (Online): 2753-8818
ISBN (Print): 978-1-80590-565-3
ISBN (Online): 978-1-80590-566-0
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Abstract

Circular RNAs (circRNAs) are covalently closed RNA molecules that were once considered transcriptional noise. Yet, in recent years, a variety of regulatory functions have been reported for circRNAs, and even more surprisingly, translation of circRNAs into microproteins has been demonstrated. This emerging field holds great promise for the field of oncology, since circRNA-encoded proteins have been increasingly implicated in processes such as proliferation, invasion, and metastasis of cancer. This review systematically summarizes the current literature on translatable circRNAs in cancer and outlines the experimental approaches commonly used for circRNA translation identification and validation. The translation of circRNAs is mediated via cap-independent mechanisms, mainly IRES and N6-methyladenosine (m⁶A) modifications. The most commonly detected circRNAs and features of their encoded microproteins are being summarized. By synthesizing these findings, this review is intended to serve as a resource for researchers in the field and to encourage further investigation into the hidden proteome and its impact on cancer.

Keywords:

Circular RNA, Cancer Proteogenomics, Internal Ribosome Entry Site, m⁶A-mediated Translation

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Zhu,Y. (2025). Hidden Proteomes: A Systematic Review of Translatable circRNAs in Oncology. Theoretical and Natural Science,152,48-55.

References

[1]. Salzman, J., Gawad, C., Wang, P.L., Lacayo, N., Brown, P.O. (2012) Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types. PLOS ONE 7: e30733

[2]. Chen, C-K., Cheng, R., Demeter, J., et al. (2021) Structured elements drive extensive circular RNA translation. Mol Cell 81: 4300-4318.e13

[3]. Hwang, H.J., Kim, Y.K. (2024) Molecular mechanisms of circular RNA translation. Exp Mol Med 56: 1272–1280

[4]. Kratka, K., Sistik, P., Olivkova, I., Kusnierova, P., Svagera, Z., Stejskal, D. (2025) Mass Spectrometry–Based Proteomics in Clinical Diagnosis of Amyloidosis and Multiple Myeloma: A Review (2012–2024). J Mass Spectrom 60: e5116

[5]. Ferreira, H.J., Stevenson, B.J., Pak, H., et al (2024) Immunopeptidomics-based identification of naturally presented non-canonical circRNA-derived peptides. Nat Commun 15: 2357

[6]. Li, H., Xie, M., Wang, Y., Yang, L., Xie, Z., Wang, H. (2021) riboCIRC: a comprehensive database of translatable circRNAs. Genome Biol 22: 79

[7]. Ye, Y., Wang, Z., Yang, Y. (2021) Comprehensive Identification of Translatable Circular RNAs Using Polysome Profiling. Bio-Protoc 11: e 4167

[8]. Fan, X., Yang, Y., Chen, C., Wang, Z. (2022) Pervasive translation of circular RNAs driven by short IRES-like elements. Nat Commun 13: 3751

[9]. Li, X., Gao, X., Zhang, N. (2022) Perspective on novel proteins encoded by circular RNAs in glioblastoma. Cancer Biol Med 19: 278

[10]. Liang, W.C., Wong, C.W., Liang, P.P., et al. (2019) Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol 20: 84

[11]. Wei, S., Zheng, Y., Jiang, Y., et al. (2019) The circRNA circPTPRA suppresses epithelial-mesenchymal transitioning and metastasis of NSCLC cells by sponging miR-96-5p. EBioMedicine 44: 182–193

[12]. Yang, Y., Gao, X., Zhang, M., et al. (2017) Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis. JNCI J Natl Cancer Inst 110: 304

[13]. Zhang. M., Zhao, K., Xu, X., et al. (2018) A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun 9: 4475

[14]. Zhang, J., Zhou, R., Zhang, H., Peng, Y., Meng, J., Xi, W., Wei, Y. (2025) Decoding circRNA translation: challenges and advances in computational method development. Front Genet 16: 1654305

[15]. Liu, Y., Zeng, S., Wu, M. (2022) Novel insights into noncanonical open reading frames in cancer. Biochim Biophys Acta Rev Cancer 1877: 188755

References

[1]. Salzman, J., Gawad, C., Wang, P.L., Lacayo, N., Brown, P.O. (2012) Circular RNAs Are the Predominant Transcript Isoform from Hundreds of Human Genes in Diverse Cell Types. PLOS ONE 7: e30733

[2]. Chen, C-K., Cheng, R., Demeter, J., et al. (2021) Structured elements drive extensive circular RNA translation. Mol Cell 81: 4300-4318.e13

[3]. Hwang, H.J., Kim, Y.K. (2024) Molecular mechanisms of circular RNA translation. Exp Mol Med 56: 1272–1280

[4]. Kratka, K., Sistik, P., Olivkova, I., Kusnierova, P., Svagera, Z., Stejskal, D. (2025) Mass Spectrometry–Based Proteomics in Clinical Diagnosis of Amyloidosis and Multiple Myeloma: A Review (2012–2024). J Mass Spectrom 60: e5116

[5]. Ferreira, H.J., Stevenson, B.J., Pak, H., et al (2024) Immunopeptidomics-based identification of naturally presented non-canonical circRNA-derived peptides. Nat Commun 15: 2357

[6]. Li, H., Xie, M., Wang, Y., Yang, L., Xie, Z., Wang, H. (2021) riboCIRC: a comprehensive database of translatable circRNAs. Genome Biol 22: 79

[7]. Ye, Y., Wang, Z., Yang, Y. (2021) Comprehensive Identification of Translatable Circular RNAs Using Polysome Profiling. Bio-Protoc 11: e 4167

[8]. Fan, X., Yang, Y., Chen, C., Wang, Z. (2022) Pervasive translation of circular RNAs driven by short IRES-like elements. Nat Commun 13: 3751

[9]. Li, X., Gao, X., Zhang, N. (2022) Perspective on novel proteins encoded by circular RNAs in glioblastoma. Cancer Biol Med 19: 278

[10]. Liang, W.C., Wong, C.W., Liang, P.P., et al. (2019) Translation of the circular RNA circβ-catenin promotes liver cancer cell growth through activation of the Wnt pathway. Genome Biol 20: 84

[11]. Wei, S., Zheng, Y., Jiang, Y., et al. (2019) The circRNA circPTPRA suppresses epithelial-mesenchymal transitioning and metastasis of NSCLC cells by sponging miR-96-5p. EBioMedicine 44: 182–193

[12]. Yang, Y., Gao, X., Zhang, M., et al. (2017) Novel Role of FBXW7 Circular RNA in Repressing Glioma Tumorigenesis. JNCI J Natl Cancer Inst 110: 304

[13]. Zhang. M., Zhao, K., Xu, X., et al. (2018) A peptide encoded by circular form of LINC-PINT suppresses oncogenic transcriptional elongation in glioblastoma. Nat Commun 9: 4475

[14]. Zhang, J., Zhou, R., Zhang, H., Peng, Y., Meng, J., Xi, W., Wei, Y. (2025) Decoding circRNA translation: challenges and advances in computational method development. Front Genet 16: 1654305

[15]. Liu, Y., Zeng, S., Wu, M. (2022) Novel insights into noncanonical open reading frames in cancer. Biochim Biophys Acta Rev Cancer 1877: 188755

Cite this article

Zhu,Y. (2025). Hidden Proteomes: A Systematic Review of Translatable circRNAs in Oncology. Theoretical and Natural Science,152,48-55.

Data availability

The datasets used and/or analyzed during the current study will be available from the authors upon reasonable request.

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Volume title: Proceedings of ICMMGH 2026 Symposium: Biomedical Imaging and AI Applications in Neurorehabilitation

ISBN: 978-1-80590-565-3(Print) / 978-1-80590-566-0(Online)
Editor: Sheiladevi Sukumaran, Alan Wang
Conference website: https://www.icmmgh.org/auckland.html
Conference date: 14 November 2025
Series: Theoretical and Natural Science
Volume number: Vol.152
ISSN: 2753-8818(Print) / 2753-8826(Online)

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