Introduction
The Research Topic entitled “RNA Helicases: Pioneering Therapeutic Avenues in Cancer Treatment” explores the emerging role of RNA helicases as central regulators of fundamental cellular processes whose dysregulation contributes to tumor initiation, progression, and therapeutic resistance. Over the last decade, increasing evidence has highlighted the importance of these enzymes not only in RNA metabolism but also in the maintenance of genome stability, cellular stress responses, and immune regulation, positioning them as attractive targets for cancer therapy.
The aim of this Research Topic is to provide new evidence supporting the functional relevance of RNA helicases as cancer-associated regulators while highlighting molecular mechanisms that may be exploited for therapeutic intervention. In addition, the Research Topic discusses emerging strategies to improve treatment efficacy by targeting RNA helicases directly or by exploiting pathways that depend on their activity.
This Research Topic includes four articles, comprising one Original Research article and three Mini-Review articles. Together, these contributions provide a comprehensive overview of the diverse biological functions of RNA helicases, including their roles in RNA processing, R-loop resolution, cellular stress responses, innate immunity, and transcriptional regulation. Collectively, the articles emphasize the remarkable functional versatility of this protein family and its growing relevance in cancer biology.
The Original Research article by Beauchemin et al., entitled “Inhibiting the RNA helicase DDX3X in Burkitt lymphoma induces oxidative stress and impedes tumor progression in xenografts,” investigated whether DDX3X, an RNA helicase frequently mutated in Burkitt lymphoma (BL), could serve as a novel therapeutic target for this disease. Using both in vitro and in vivo experimental models, the authors demonstrated that pharmacological inhibition of DDX3X with RK-33, as well as genetic depletion of the helicase, significantly reduced tumor progression by inducing cellular stress responses and impairing cancer cell survival. Furthermore, a CRISPR-based chemogenomic screen identified the glutathione synthesis pathway as a critical determinant of sensitivity to DDX3X inhibition. Notably, suppression of glutathione production enhanced the cytotoxic effects of RK-33, suggesting a potential combination strategy to improve therapeutic efficacy in BL.
The three Mini-Review articles focus on the biological functions of RNA helicases and their interaction partners, including the histone methyltransferase EHMT2, the fusion oncoprotein PAX3-FOXO1, adenosine deaminase acting on RNA 1 (ADAR1), and several factors involved in R-loop resolution. These reviews highlight the growing evidence supporting RNA helicases as promising therapeutic targets across different cancer types.
The first Mini Review, by Bianconi and Mozzetta, entitled “Unwinding New Therapeutic Opportunities in Rhabdomyosarcoma: The Role of RNA Helicase DDX5,” discusses the role of DDX5 as a key oncogenic regulator in rhabdomyosarcoma (RMS), particularly in the aggressive fusion-positive alveolar subtype (). DDX5 promotes tumor growth and survival by stabilizing oncogenic pathways involving EHMT2 and PAX3-FOXO1 () and by cooperating with YTHDC1 to enhance the biogenesis of cancer-associated circular RNAs (). Given its overexpression and functional importance in RMS cells, DDX5 represents an attractive therapeutic target. The review also discusses emerging DDX5 inhibitors, including RX-5902, which may offer new opportunities for targeted treatment approaches in RMS.
The second Mini Review, by Minakuchi et al., entitled “Orchestrating Innate Immunity Through RNA Editing and Helicase Activity: ADAR1, dsRNA Sensors, and Tumor Immune Evasion,” examines the role of ADAR1 as a key RNA-editing enzyme that maintains cellular double-stranded RNA (dsRNA) homeostasis. Accumulation of endogenous dsRNA can activate innate immune pathways, leading to inflammatory responses and cell death (). ADAR1 prevents inappropriate immune activation by catalyzing adenosine-to-inosine (A-to-I) editing of endogenous dsRNA molecules. The review provides a detailed overview of A-to-I RNA editing and highlights how ADAR1 cooperates with RNA helicases, including DDX3X and DHX9, to regulate dsRNA sensing and immune signaling. These findings have important implications for cancer therapy, particularly in the context of immunomodulatory approaches.
The third Mini Review, by Herrera et al., entitled “Targeting R-loops: Diverse RNA Helicases in R-loop Resolution and Their Potential as Targets for Cancer Therapy,” focuses on the critical role of RNA helicases in maintaining genome stability through the resolution of R-loops. The authors summarize evidence demonstrating that defects in R-loop resolution lead to replication stress, DNA damage, transcriptional abnormalities, and genomic instability, all of which are hallmarks of cancer (; ). The review highlights a growing list of RNA helicases involved in R-loop metabolism and discusses how understanding their recruitment mechanisms and substrate specificity may reveal new therapeutic vulnerabilities in cancer cells.
Overall, RNA helicases have emerged as key multifunctional regulators of RNA processing and cellular homeostasis whose activities are frequently altered in cancer. The objective of this Research Topic was to provide an updated perspective on the biological functions of RNA helicases and to evaluate their potential as therapeutic targets. The four contributions published in Frontiers in Cell and Developmental Biology significantly advance our understanding of RNA helicase biology and its possible clinical translation.
We anticipate that this Research Topic will be of interest to a broad readership, including basic researchers, translational scientists, and clinicians working in oncology and RNA biology. Nevertheless, these articles address only a fraction of the many unresolved questions surrounding the diverse and context-dependent functions of RNA helicases. Further investigations will be essential to elucidate the molecular mechanisms governing helicase activity, identify predictive biomarkers of response, and develop more selective and effective therapeutic strategies with reduced toxicity. Continued research in this rapidly evolving field is expected to uncover new opportunities for targeting RNA helicases and their associated pathways in cancer treatment.
Statements
Author contributions
LC: Writing – review and editing, Writing – original draft. TM: Writing – original draft, Writing – review and editing.
Funding
The author(s) declared that financial support was not received for this work and/or its publication.
Conflict of interest
The author(s) declared that this work was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Generative AI statement
The author(s) declared that generative AI was not used in the creation of this manuscript.
Any alternative text (alt text) provided alongside figures in this article has been generated by Frontiers with the support of artificial intelligence and reasonable efforts have been made to ensure accuracy, including review by the authors wherever possible. If you identify any issues, please contact us.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
ChenY. G.HurS. (2022). Cellular origins of dsRNA, their recognition and consequences. Nat. Rev. Mol. Cell. Biol.23, 286–301. 10.1038/s41580-021-00430-1
2
DattiloD.Di TimoteoG.SettiA.GiulianiA.PeruzziG.et al (2023). The m6A reader YTHDC1 and the RNA helicase DDX5 control the production of rhabdomyosarcoma-enriched circRNAs. Nat. Commun.14 (1), 12–15. 10.1038/s41467-023-37578-7
3
GualtieriA.BianconiV.RenziniA.PieroniL.LicursiV.MozzettaC. (2022). The RNA helicase DDX5 cooperates with EHMT2 to sustain alveolar rhabdomyosarcoma growth. Cell. Rep.40 (9), 111267. 10.1016/j.celrep.2022.111267
4
NiehrsC.LukeB. (2020). Regulatory R-loops as facilitators of gene expression and genome stability. Nat. Rev. Mol. Cell. Biol.21, 167–178. 10.1038/s41580-019-0206-3
5
YangS.WinstoneL.MondalS. (2023). Helicases in R-loop formation and resolution. J. Biol. Chem.299, 105307. 10.1016/j.jbc.2023.105307
Summary
Keywords
cancer therapy, DEAD/DExH-box, gene expression, R-loop, RNA helicase
Citation
Chellini L and Murayama T (2026) Editorial: RNA helicases: pioneering therapeutic avenues in cancer treatment. Front. Cell Dev. Biol. 14:1900371. doi: 10.3389/fcell.2026.1900371
Received
04 June 2026
Accepted
06 July 2026
Published
14 July 2026
Volume
14 - 2026
Edited and reviewed by
Philippe P. Roux, Université de Montréal, Canada
Updates
Copyright
© 2026 Chellini and Murayama.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Lidia Chellini, chellinilidia@gmail.com; Takahiko Murayama, takahiko.murayama@downstate.edu
† These authors have contributed equally to this work
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.