A new review in Genes & Diseases examines how circular RNAs, or circRNAs, could help scientists understand and control one of oncology’s most persistent problems: the toxic effects of cancer treatment. Chemotherapy, radiotherapy and immunotherapy have transformed cancer care, extending survival for millions of people. Yet these treatments can also damage healthy tissues, producing complications that range from temporary discomfort to permanent organ dysfunction. The review argues that circRNAs may offer a new molecular framework for predicting, monitoring and potentially reducing these adverse effects.
CircRNAs are a distinctive class of RNA molecules formed when a strand of RNA is joined end to end through a process known as back-splicing. Unlike conventional messenger RNAs, which typically have exposed ends and are rapidly degraded, circRNAs form stable closed loops. This structure gives them unusual resistance to cellular enzymes called exonucleases, allowing them to persist in cells, tissues and body fluids for extended periods. Their stability, combined with tissue-specific patterns of expression, has made circRNAs increasingly attractive to researchers searching for reliable biomarkers of disease and treatment response.
Although they do not usually encode proteins, circRNAs can influence gene activity through several mechanisms. Some act as molecular sponges by binding microRNAs and preventing those small regulatory molecules from suppressing their target genes. Others interact directly with RNA-binding proteins, affecting their location or function, while certain circRNAs influence transcription and the processing of other RNA molecules. A subset can even be translated into short peptides. Through these activities, circRNAs can regulate oxidative stress, inflammatory signaling, programmed cell death, mitochondrial function and DNA repair—all processes closely linked to treatment-induced tissue injury.
The review describes circRNAs as having a dual role in cancer-treatment toxicity. In some circumstances, they intensify damage by promoting inflammatory pathways, increasing the production of reactive oxygen species or weakening the cell’s antioxidant defenses. Excessive reactive oxygen species can attack proteins, lipids and DNA, while mitochondrial dysfunction can deprive cells of energy and trigger apoptosis. In other situations, circRNAs appear to protect healthy cells by maintaining mitochondrial stability, limiting inflammatory responses or activating pathways that support cellular repair and survival. The biological outcome therefore depends on the specific circRNA, the tissue involved and the treatment exposure.
The heart is one of the organs most vulnerable to certain anticancer drugs, including agents that can impair cardiac muscle function. According to the review, circRNAs may participate in cardiotoxicity by regulating oxidative imbalance, mitochondrial injury, fibrosis and inflammatory signaling in cardiac cells. Some circRNA expression patterns have been associated with protection against cell death, whereas others may contribute to the progressive loss of cardiac function. If these molecular signatures can be validated in patients, blood-based circRNA measurements could eventually help identify individuals at heightened risk before clinically obvious cardiotoxicity develops.
Similar mechanisms are being investigated in the kidneys, nervous system and gastrointestinal tract. Nephrotoxic treatments can disrupt renal tubular cells through oxidative stress, inflammation and mitochondrial damage, while neurotoxic agents may interfere with neuronal survival and the function of supporting glial cells. Radiation and systemic therapies can also injure the intestinal lining, alter barrier integrity and provoke inflammatory reactions. Because circRNAs can be released into extracellular vesicles such as exosomes, they may travel between cells and coordinate responses across tissues. Their presence in circulating fluids provides a potential route for detecting injury without repeated invasive procedures.
CircRNAs may also be relevant to immune-related adverse events caused by modern immunotherapies. Drugs that block immune checkpoints can restore the ability of T cells to attack tumors, but they may also trigger excessive immune activity against normal organs. The resulting inflammation can affect the heart, lungs, liver, intestines, skin and endocrine tissues. By regulating cytokine production, immune-cell activation and intracellular inflammatory pathways, circRNAs could help explain why some patients tolerate immunotherapy well while others develop severe complications. Their measurement might one day support more individualized decisions about treatment intensity, surveillance and the use of anti-inflammatory interventions.
The therapeutic possibilities extend beyond using circRNAs as warning signals. Researchers are exploring whether harmful circRNAs could be silenced with antisense oligonucleotides or other RNA-targeting technologies, while protective circRNAs might be delivered to injured tissues using nanoparticles or engineered extracellular vesicles. Such approaches remain experimental, and any intervention would need to preserve the anticancer activity of treatment while protecting normal cells. A therapy that reduces toxicity but also shields tumor cells would not be clinically useful. The central challenge is therefore to identify circRNA pathways that are selective for healthy-tissue protection rather than tumor survival.
Considerable obstacles stand between these discoveries and routine clinical use. CircRNA detection requires highly sensitive methods capable of distinguishing circular molecules from similar linear RNA transcripts. Differences in sample collection, RNA extraction, sequencing platforms and data analysis can produce inconsistent results between laboratories. Researchers must also determine whether a change in circRNA levels is a direct cause of tissue injury, a consequence of it or simply a marker of broader cellular stress. Large, well-designed clinical studies will be needed to connect specific circRNA signatures with treatment dose, timing, organ damage and long-term outcomes. Nevertheless, the review presents circRNA biology as a promising frontier in precision oncology, with the potential to make cancer treatment safer without sacrificing its effectiveness.
Subject of Research: Circular RNAs and their roles in cancer-therapy-induced toxicity, including cardiotoxicity, nephrotoxicity, neurotoxicity, gastrointestinal injury and immune-related adverse events.
Article Title: Role of circular RNAs in regulating toxicity induced by cancer therapies
Web References: https://doi.org/10.1016/j.gendis.2025.101982; https://www.sciencedirect.com/journal/genes-and-diseases
References: Jiawen Xian, Javeria Qadir, Burton B. Yang, Ting Ye, “Role of circular RNAs in regulating toxicity induced by cancer therapies,” Genes & Diseases, Volume 13, Issue 4, 2026, Article 101982. DOI: 10.1016/j.gendis.2025.101982
Image Credits: Genes & Diseases
Keywords: circular RNAs; circRNAs; cancer therapy; treatment toxicity; chemotherapy; radiotherapy; immunotherapy; cardiotoxicity; nephrotoxicity; neurotoxicity; gastrointestinal injury; biomarkers; oxidative stress; mitochondrial dysfunction; precision oncology
Tags: back-splicing process in circRNA formationcircRNA biomarkers for treatment responsecircRNA mechanisms in gene regulationcircRNAs and radiotherapy adverse effectscircRNAs as stable molecular biomarkerscircRNAs in predicting organ dysfunction post-treatmentcircular RNAs in cancer therapy toxicitymolecular pathways of circRNAs in cancerpotential of circRNAs to improve immunotherapy safetyreducing chemotherapy side effects with circRNAsrole of circRNAs as therapeutic targets in oncologytissue-specific circRNA expression in oncology
