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Exosomal circRNAs in hepatocellular carcinoma: Implications for the development and therapeutic resistance of hepatocellular carcinoma (Review)

  • Authors:
    • Zhiyao Liu
    • Yuqiao Wang
    • Yali Wang
    • Yucheng Zhang
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    Affiliations: Second Division of Department of Oncology, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130031, P.R. China, Department of Orthopedics, The First Affiliated Hospital of Chongqing Medical University, Orthopedic Laboratory of Chongqing Medical University, Chongqing 400016, P.R. China, Department of Blood Transfusion, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China, Scientific Research Center, China‑Japan Union Hospital of Jilin University, Changchun, Jilin 130033, P.R. China
    Copyright: © Liu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Article Number: 26
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    Published online on: December 16, 2025
       https://doi.org/10.3892/ijo.2025.5839
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Abstract

Hepatocellular carcinoma (HCC) is the predominant type of primary liver cancer, with high morbidity and mortality rates globally, ranking it among the leading causes of cancer‑related death worldwide. Despite notable advancements in HCC treatment in recent years, high rates of recurrence and treatment resistance remain significant clinical challenges. The development of drug resistance undermines the efficacy of current therapies and leads to poor patient outcomes. However, the specific role and detailed delivery mechanism of exosomal circular RNAs (circRNAs) in mediating this treatment resistance are still largely undefined. circRNAs represent a group of non‑coding RNAs with various biological roles. An increasing number of circRNAs are abnormally expressed in HCC and participate in the malignant progression of HCC, playing a role in HCC treatment resistance. Furthermore, circRNAs can exert additional effects when packaged into exosomes. Exosomes, as signaling molecules of intercellular communication, are enriched with circRNAs, which can be packaged, secreted and transferred to target recipient tumor cells, thereby regulating the development process and drug resistance of cancer. The present comprehensive review aims to summarize how these exosomal circRNAs regulate key hallmarks of cancer in HCC and critically synthesize the current literature, elucidating how exosomal circRNAs modulate therapeutic resistance in HCC and highlighting their potential as biomarkers and therapeutic targets.
View Figures

Figure 1

Schematic illustrating the formation
and secretion process of exosomes as well as their structure.
Secretory cells form early endosomes through inward budding, which
gradually evolve into mature MVBs. These MVBs fuse with the plasma
membrane to release exosomes. Exosomes contain bioactive substances
such as DNA, mRNA, miRNA, circRNA, proteins and lipids. These
components are delivered to recipient cells via endocytosis,
enabling them to exert biological effects. The primary biological
functions of circRNAs include. (A) Interacting with RBPs to
regulate gene expression (B) acting as competing sponges for miRNAs
to modulate target gene expression (C) serving as protein scaffolds
to facilitate interactions between different proteins (D) some
circRNAs can be translated by ribosomes into protein polypeptides
to perform regulatory functions; and (E) binding to U1 snRNP, which
forms complexes with RNA polymerase II to regulate gene
transcription or splicing. circRNA, circular RNA; ER, endoplasmic
reticulum; RBPs, RNA-binding protein; MVBs, multivesicular bodies;
IVLs, intraluminal vesicle; IRES, internal ribosome entry site;
ORF, open reading frame; U1 snRNP, U1 small nuclear
ribonucleoprotein particles. Figure was created with biorender.com.

Figure 2

Biogenesis and function of circRNAs.
circRNAs are primarily generated from pre-mRNA through
back-splicing, which encompasses three unique mechanisms: i) Intron
pairing-driven cyclization, which depends on base-pairing
interactions between reverse complementary sequences, such as ALU
repeats, found in the introns adjacent to exons; ii) RBP-mediated
cyclization utilizes the involvement of RBPs to bring splicing
sites closer together, thereby facilitating the creation of
circRNAs; iii) lariat-driven cyclization aids in forming an
exon-containing lariat structure during exon skipping events,
leading to the production of EIciRNA or ecircRNA; and iv) the
generation of tricRNAs occurs through the enzymatic cleavage of
pre-tRNA, yielding tricRNAs and the remaining fragment which is
further processed into mature tRNAs. The functions of circRNAs can
be categorized into the following five classes. (A) Regulation of
RNA transcription (B) acting as sponges for RBPs (C) acting as
sponges for miRNAs (D) functioning as protein scaffolds; and (E)
translation of proteins. circRNA, circular RNA; EIciRNA,
exon-intron circRNA; EcircRNA, exonic circRNA; ciRNA, intronic
circRNA; TricRNA, tRNA intronic circular RNA; U1 snRNP, U1 small
nuclear ribonucleoprotein particles. Figure was created with
biorender.com.

Figure 3

Effects of exosomal circRNAs on the
initiation and progression of HCC. (A) Exosomal circRNAs can either
promote or inhibit HCC cell proliferation; (B) exosomal circRNAs
can may enhance or suppress HCC invasion and metastasis; (C)
exosomal circRNAs can either facilitate or attenuate the apoptotic
process in HCC cells; (D) exosomal circRNAs can drive metabolic
reprogramming in HCC cells; (E) exosomal circRNAs can augment the
self-renewal capacity of HCC cells and enhance the expression of
their stem cell phenotype; and (F) exosomal circRNAs can promote
the angiogenic capacity of HCC. HCC, hepatocellular carcinoma;
circRNA, circular RNA. Figure was created with biorender.com.

Figure 4

Exosomal circRNAs related to
therapeutic resistance in HCC. The mechanism of representative
exosomal circRNAs that show regulatory effects in chemotherapy,
radiotherapy, targeted therapy and immunotherapy resistance of HCC.
circRNA, circular RNA; SLC7A11, solute carrier family 7 member 11;
IGF2BP2, insulin-like growth factor 2 mRNA-binding protein 2;
USP28, ubiquitin specific peptidase 28; YAP, Yes-associated
protein; NAP1L1, nucleosome assembly protein 1 like 1; EMT,
epithelial-mesenchymal transition; Ku70, Ku autoantigen, 70kD.
Figure was created with biorender.com.
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Copy and paste a formatted citation
Spandidos Publications style
Liu Z, Wang Y, Wang Y and Zhang Y: Exosomal circRNAs in hepatocellular carcinoma: Implications for the development and therapeutic resistance of hepatocellular carcinoma (Review). Int J Oncol 68: 26, 2026.
APA
Liu, Z., Wang, Y., Wang, Y., & Zhang, Y. (2026). Exosomal circRNAs in hepatocellular carcinoma: Implications for the development and therapeutic resistance of hepatocellular carcinoma (Review). International Journal of Oncology, 68, 26. https://doi.org/10.3892/ijo.2025.5839
MLA
Liu, Z., Wang, Y., Wang, Y., Zhang, Y."Exosomal circRNAs in hepatocellular carcinoma: Implications for the development and therapeutic resistance of hepatocellular carcinoma (Review)". International Journal of Oncology 68.2 (2026): 26.
Chicago
Liu, Z., Wang, Y., Wang, Y., Zhang, Y."Exosomal circRNAs in hepatocellular carcinoma: Implications for the development and therapeutic resistance of hepatocellular carcinoma (Review)". International Journal of Oncology 68, no. 2 (2026): 26. https://doi.org/10.3892/ijo.2025.5839
Copy and paste a formatted citation
x
Spandidos Publications style
Liu Z, Wang Y, Wang Y and Zhang Y: Exosomal circRNAs in hepatocellular carcinoma: Implications for the development and therapeutic resistance of hepatocellular carcinoma (Review). Int J Oncol 68: 26, 2026.
APA
Liu, Z., Wang, Y., Wang, Y., & Zhang, Y. (2026). Exosomal circRNAs in hepatocellular carcinoma: Implications for the development and therapeutic resistance of hepatocellular carcinoma (Review). International Journal of Oncology, 68, 26. https://doi.org/10.3892/ijo.2025.5839
MLA
Liu, Z., Wang, Y., Wang, Y., Zhang, Y."Exosomal circRNAs in hepatocellular carcinoma: Implications for the development and therapeutic resistance of hepatocellular carcinoma (Review)". International Journal of Oncology 68.2 (2026): 26.
Chicago
Liu, Z., Wang, Y., Wang, Y., Zhang, Y."Exosomal circRNAs in hepatocellular carcinoma: Implications for the development and therapeutic resistance of hepatocellular carcinoma (Review)". International Journal of Oncology 68, no. 2 (2026): 26. https://doi.org/10.3892/ijo.2025.5839
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