Jul 2026· Journal of Translational Medicine· 1 citation
Medicine
TL;DR
By integrating molecular mechanisms with clinical perspectives, this review charts a roadmap for targeting the epitranscriptomic-long non-coding RNA circuit in precision oncology.
Abstract
Background
Long non-coding RNAs and N6-methyladenosine RNA methylation represent two pivotal layers of gene regulation. Their extensive crosstalk forms a sophisticated bidirectional network that is fundamentally rewired in cancer.
MAIN BODY
This review synthesizes current knowledge to elucidate the principles and consequences of this synergistic axis. We detail how m6A modification dictates long non-coding RNA stability, splicing, localization, and function through recruitment of distinct "reader" proteins, with one "reader" family primarily mediating decay while another promotes stabilization. Conversely, we examine how long non-coding RNAs act as scaffolds, guides, and decoys to modulate the activity and specificity of the m6A machinery, establishing powerful feedforward and feedback loops. This reciprocal regulation converges on multiple cancer hallmarks, including proliferation, metabolic reprogramming, immune evasion, stemness, and therapeutic resistance. We critically discuss experimental strategies to establish causal relationships, including site-directed mutagenesis, CRISPR-based editing, and rescue assays. We also evaluate current methodological limitations in m6A detection, from antibody-dependent approaches to emerging nanopore sequencing, and highlight how single-cell and spatial transcriptomic technologies can resolve cell-state-specific networks within the tumor microenvironment. From a translational perspective, we compare small molecule inhibitors targeting m6A "writers" with RNA-based therapies, addressing their respective delivery challenges and toxicity concerns. Finally, we outline how m6A-related long non-coding RNA signatures serve as prognostic biomarkers and liquid biopsy tools for non-invasive cancer monitoring.
Conclusion
By integrating molecular mechanisms with clinical perspectives, this review charts a roadmap for targeting the epitranscriptomic-long non-coding RNA circuit in precision oncology.
Hepatocellular carcinoma (HCC) is a malignant neoplasm characterized by high incidence and mortality rates globally. Its pathogenesis and progression are intricate and multifaceted, necessitating comprehensive analysis and elucidation. Recent studies have demonstrated that non-coding RNAs (such as long non-coding RNAs, circular RNAs, and microRNAs) and alternative splicing, which are central to post-transcriptional regulation, engage in extensive regulatory interactions. These interactions form a complex regulatory network that significantly influences the malignant properties such as stemness, proliferation, invasion, metastasis, metabolic reprogramming, tumor microenvironment, and drug sensitivity in liver cancer cells. This review systematically explores the molecular mechanisms underlying the interactions between non-coding RNAs and alternative splicing events, highlighting the role of this regulatory network in modulating the expression of oncogenes and tumor suppressor genes in HCC. Additionally, this review investigates the prospective application of pivotal molecules within this regulatory network as novel diagnostic biomarkers and therapeutic targets. It also analyzes the challenges and obstacles encountered in the clinical translation process, thereby providing new insights for research on the precision diagnosis and treatment of HCC.
Y-box binding protein 1 (YBX1) has been implicated across an unusually broad range of malignancies and processes: immune remodeling, epithelial plasticity, metabolic rewiring, epitranscriptomic reading, and resistance to chemotherapy, targeted agents, and checkpoint blockade. A linear one-gene/one-pathway oncogene model does not readily accommodate this breadth. We argue that the apparent diffuseness reflects a context-dependent regulatory node rather than experimental noise, and develop the hypothesis that YBX1 acts as an
adaptive RNA/transcriptional hub
, a regulator whose transcript outputs are set by cellular state rather than by a fixed binding program, which acts in both the transcriptional and post-transcriptional compartments, and which sits inside feedback loops linking downstream metabolic states back to its own activity. We organize the literature into three coupled layers: a state code, in which post-translational modifications, ubiquitin balance, localization, and phase separation determine which YBX1 is active (Layer 1); an RNA program, in which m5C reading and non-coding-RNA scaffolds are associated with a restricted survival transcriptome (Layer 2); and the immune, metabolic, and plasticity phenotypes these outputs generate (Layer 3). Evidence further suggests that tumor-specific dependency is carried by the configuration of the YBX1/YBX2/YBX3 family rather than by any single member. We specify what would falsify the framework: if state-resolved readouts do not predict downstream circuit activity better than total YBX1 abundance, the hub reduces to a promiscuous, abundant RNA-binding protein whose correlations are epiphenomenal. We give explicit weight to evidence resisting an oncogenic reading: circuits in which restraining YBX1 is tumor-suppressive, non-coding-RNA and family-level interactions running in opposite directions, and effectors regulated divergently between tumors, treating these as boundary conditions rather than exceptions. This reframing shifts the actionable question from whether YBX1 is high to which YBX1-dependent circuit a tumor uses; its value remains contingent on prospective, state- and circuit-level validation.
Cancer remains a major global health burden, with its incidence and mortality rates persistently high despite advances in treatment. Despite therapeutic innovations, malignant tumors continue to pose a formidable challenge to global health. Against this backdrop, the crosstalk between long non-coding RNAs (lncRNAs) and the Notch signaling pathway has emerged as a pivotal driver of tumorigenesis and progression. However, the complex regulatory network and a comprehensive mechanistic framework of this axis await systematic elucidation. This review systematically consolidates recent advances in understanding how lncRNAs precisely modulate Notch pathway activity through diverse mechanisms, including acting as competing endogenous RNAs, direct protein binding, epigenetic regulation, and exosome-mediated intercellular communication. The discussion encompasses various malignancies, spanning the digestive, respiratory, urogenital, nervous, and hematologic systems. The lncRNA-Notch regulatory axis is identified as a ubiquitous and functionally central oncogenic network. It orchestrates critical malignant phenotypes—such as such as stemness maintenance, epithelial-mesenchymal transition, metabolic shifts, drug resistance, and immune evasion—through intricate bidirectional crosstalk. Functional studies confirm that targeting key nodes of this axis can effectively reverse drug resistance and suppress tumor growth. Although challenges remain in its clinical translation, future research integrating single-cell multi-omics, nanotechnology, and other innovative strategies will undoubtedly open new avenues for precision diagnosis and cancer therapy.
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