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Singh et al. Cancer Drug Resist. 2025;8:56 Page 3 of 20

to reliably differentiate tumor-derived circRNAs from circRNAs in normal tissues . Fourth, circRNAs with
[21]
significant clinical value must be further validated in extensive, multi-center translational studies and
matched to numerous cancer types and treatment approaches . The detection of circulating circRNAs using
[22]
liquid biopsy represents a watershed innovation in cancer diagnostics and therapeutic monitoring .
[22]
Real-time detection of molecular underpinnings of drug resistance would enhance personalized treatment
through circRNA profiling to guide drug choice and ultimately improve patient outcomes . As this exciting
[23]
field develops further, circRNA biomarkers are expected to be integrated into clinical practice, facilitating
more adaptive cancer care within the context of personalized medicine.

CIRCRNAS FOR TRACKING DRUG RESISTANCE IN CANCER
CircRNAs are generated from pre-mRNA transcripts through a unique phenomenon known as
back-splicing. Back-splicing is an event where a downstream splice donor connects to an upstream splice
acceptor . Back-splicing can occur with the help and support of RBP or inverted repeat elements -
[24]
sequences that bring exons into close proximity, enabling their circularization . The resulting circRNAs
[25]
consist of covalently closed loop structures and therefore lack 5′ caps or 3′ poly (A) tails . The absence of
[26]
these terminal modifications contributes to the very high stability of circRNAs compared with linear RNAs
[Figure 1] . CircRNAs can additionally stabilize protein complexes, as demonstrated by circACC1, which
[27]
aids in the assembly of the adenosine monophosphate (AMP) kinase complex and has a role in
metabolism . CircRNAs have also been associated with promoting proliferation, survival, and resistance to
[28]
therapy in cancer cells by interacting with major signal transduction pathways . They are not commonly
[29]
involved in the regulation of transcription in the nucleus; however, there is an emerging role (either positive
or negative) for some circRNAs to direct gene expression in multiple ways [Figure 1] . Once formed,
[30]
circRNAs will be exported from the nucleus to the cytoplasm via nuclear pores . Once in the cytoplasm,
[31]
they will exert many biological functions. One of the most reported is miRNA sponging . CircRNAs
[32]
contain multiple binding sites for specific miRNAs. By binding these miRNAs, circRNAs can sequester them
away from their target mRNAs and all their splicing isoforms, thereby inhibiting their regulatory effects .
[32]
For example, ciRS-7 acts specifically as a sponge for the miR-7 pathway, affecting oncogenic pathways.
Studies have established certain circRNAs, such as circHIPK3, circFOXO3, and circRNA_100290, which can
modulate some cancer pathways and affect chemotherapy sensitivity . CircHIPK3 is one of the well-studied
[32]
circRNAs and has been reported to be overexpressed in colorectal, lung, and bladder cancer . This circRNA
[33]
functions as a sponge for multiple tumor-suppressive miRNAs, such as miR-124 and miR-558, and promotes
cell proliferation and chemoresistance to 5-fluorouracil (5-FU) and cisplatin . Another significant circRNA
[34]
is circRNA forkhead box O3 (circFOXO3), which has been shown to bind to cyclin-dependent kinase 2
(CDK2) and p21, and affect cell cycle regulation and apoptosis in breast and lung cancer. Dysregulation of
circFOXO3 has also been implicated with chemoresistance and poor clinical outcomes . CircRNA
[35]
plasmacytoma variant translocation 1 (Circ-PVT1) participates in paclitaxel resistance in gastric cancer as a
sponge for miR-124-3p and regulates the EMT marker zinc finger E-box-binding homeobox 1 (ZEB1), thus
promoting invasive and drug-resistant phenotypes; circ-MTO1 in hepatocellular carcinoma (HCC)
promotes doxorubicin sensitivity by sponging miR-9 and upregulating the tumor suppressor p21, and its
downregulation correlates with increased resistance and poorer prognosis . Circ-AKT3 regulates
[36]
temozolomide (TMZ) resistance in glioblastoma (GBM) by regulating the phosphoinositide 3-kinase
(PI3K)/protein kinase B (AKT) pathways and cancer stem cell characteristics . Circ-ABCB10, another
[37]
extensively studied circRNA, provides resistance to multiple drugs in lung and breast cancer by regulating
B-cell lymphoma 2 (BCL2) through the modulation of miR-1271 . As circRNAs continue to advance, future
[18]
endeavors should address resistance issues, such as integrating circRNA panels into monitoring workflows,
and further evaluating and validating circRNAs as therapeutic targets to reverse drug resistance and improve
patient outcomes . Key circRNAs implicated in cancer drug resistance, along with their pathways,
[9]
mechanisms, and clinical applications, are presented in Table 1.

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