Time to Study the RNA Itself: Rebalancing the Non-Coding RNA Research Agenda

Twenty years ago, long non-coding RNAs were dismissed as transcriptional noise, and circular RNAs were a curiosity of molecular biology. Today, the picture has changed beyond recognition. Annotated lncRNA genes in the human genome already outnumber protein-coding genes, circRNAs have their own back-splicing biology and an early position in clinical development, and lncRNA- and circRNA-based therapeutics are now in clinical pipelines. Yet according to a new Editorial published in Experimental & Molecular Medicine, much of the research being published on these molecules today follows a strikingly uniform template, and the field risks mistaking repetition for discovery.

The Editorial, published on 9 July 2026, argues that the most productive open questions in lncRNA and circRNA biology lie not in yet another downstream target study, but in the intrinsic biology of the RNA molecules themselves. What controls their expression, what shape they take, how they are produced, how much of them is actually present in a cell, and which exact isoform is being studied. The authors call this a shift in perspective, and they argue it is not merely of biochemical interest but ultimately determines the clinical relevance of the entire field.

The evidence for this concern comes from a retrospective analysis of 35 lncRNA and circRNA research papers published in Experimental & Molecular Medicine over the past decade, from June 2016 to May 2026. Of these, 15 papers, or 43 percent, proposed competitive endogenous RNA or miRNA sponging mechanisms, while another 16 papers, or 46 percent, described lncRNA-protein binding events characterized primarily through pull-down and luciferase assays. Only one paper addressed any of the five underexplored areas highlighted in the Editorial, and not a single paper made biogenesis, RNA structure, absolute quantification or isoform-specific function a primary mechanistic claim.

The competitive endogenous RNA hypothesis, which proposes that an RNA can act as a molecular sponge for microRNAs, was challenged on quantitative grounds more than 10 years ago. Many lncRNAs are present at copy numbers far too low to titrate cellular miRNA pools meaningfully. Single-molecule fluorescence in situ hybridization and absolute quantification studies have shown that roughly 40 percent of lncRNAs are present at ten or fewer copies per cell. Most canonical sponge or scaffold mechanisms simply cannot operate at those concentrations. Yet the template has remained remarkably common in the literature, with a new RNA reported as differentially expressed in a disease, knocked down to produce a phenotype in one or two cell lines, confirmed in an animal model, shown in a small patient cohort, and then assigned a predicted microRNA target confirmed by luciferase assay.

The authors are careful to say that these mechanisms are not wrong. The principles of ceRNA and lncRNA-protein interactions are real biological phenomena that have advanced the field. The concern is not with the ceRNA concept itself, but with how often it is invoked as a default mechanism without sufficient quantitative or mechanistic support. A study that repeats this familiar flow under a new RNA name, even with the now standard combination of cell line, animal and patient sample data, adds relatively little that is conceptually new. Multi-system validation has become the baseline expectation rather than a mark of distinction, and for research to be truly novel, more is required than ever before.

The first underexplored area is upstream regulation of long non-coding RNAs. There is a clear asymmetry in the literature. Many papers describe what an lncRNA regulates, but very few ask what regulates the lncRNA itself. Genome-wide analyses have shown that lncRNA promoters carry distinct transcription factor binding patterns, which implies that lncRNAs operate under their own regulatory programme. For most disease-associated lncRNAs, however, we still do not know which transcription factors actually drive them, which signals turn them on, or why their expression is restricted to particular tissues or disease states. The post-transcriptional layer is similarly underdeveloped. LncRNAs are typically short-lived, and their turnover by the nuclear and cytoplasmic surveillance machinery is what really sets their steady-state abundance, but this is rarely the focus of mechanistic studies.

The second area is biogenesis and the host gene relationship of circular RNAs. Almost every circRNA paper asks what the circRNA does, but very few ask why the back-splicing event happened in the first place. The answer involves cis elements such as flanking inverted repeats and intron length asymmetry, together with a growing set of trans-acting RNA-binding proteins, but the catalogue is far from complete. Biogenesis is also highly context dependent. Stresses such as hypoxia, DNA damage, and immune activation reshape the back-splicing landscape, often in dramatic ways, and the mechanisms behind those shifts are mostly unknown. The relationship between a circRNA and its host gene is a second open question. We rarely know whether the two are coupled or independent, whether circRNA production comes at the expense of linear mRNA from the same locus, or whether the circRNA feeds back on its own host. The same set of questions applies to divergent, antisense and intronic lncRNAs, where it is often unclear whether the act of transcription, the RNA product, or both, carries the function.

The third area is structure and function. Protein biochemistry accepted long ago that mechanism cannot be claimed without structure, but research on lncRNAs and circRNAs has been slower to adopt this standard. Most papers infer function from sequence and binding partners, with no information about the secondary or tertiary structure that actually supports those interactions. The tools have been available for years. In-cell chemical probing methods now map RNA structure at nucleotide resolution across the transcriptome, cryogenic electron microscopy of ribonucleoprotein particles is now routine for many complexes, and computational structure prediction has improved enough to be a useful starting point. Studies that map the structural modules of an lncRNA or circRNA, identify the elements that drive its protein interactions, and test how RNA modifications change folding will move the field towards a genuine mechanism, and will also establish the foundation that any RNA-targeted therapeutic effort will eventually need.

The fourth area is quantitative biology. Mechanism is a quantitative claim. A proposed sponge or scaffold function requires the regulator to be present at a concentration high enough to engage its targets. The same level of quantitative rigour applied for years in studies of transcription factors and signalling pathways could valuably be extended to lncRNA and circRNA research. The fifth area is isoform identity. A single lncRNA locus often produces several isoforms with different ends, splice patterns and polyadenylation sites, and a single circRNA host gene can give rise to dozens of distinct circular products. The literature still routinely refers to a given lncRNA or circRNA as if it were a single, uniform molecule. Defining which isoform actually does the work, in which cell type and under which conditions, should be treated as a prerequisite for a mechanistic claim, not as an optional refinement. Long-read sequencing, isoform-specific perturbation and isoform-resolved expression analysis have made this practical.

The broader point is that none of this implies classical ceRNA and descriptive lncRNA-protein interaction studies no longer have a place. Rather, such studies are most valuable when they meet a higher bar than has often been applied. A proposed mechanism is more convincing when it is quantitatively plausible, not merely consistent with what is already known. Binding interactions are more compelling when shown to be direct rather than inferred from prediction tools alone. The authors hope that work taking up any of the directions sketched above, or other emerging directions aligned with this shift towards the lncRNA or circRNA itself, will help to shape where the field goes next. The essential question for authors is what makes their work a substantive advance over the existing literature, rather than a familiar story with a new RNA name attached.

Subject of Research: Rebalancing the non-coding RNA research agenda towards upstream regulation, biogenesis, structure, quantitative biology and isoform identity

Article Title: Rebalancing the non-coding RNA research agenda: future directions for long non-coding RNA and circular RNA research

Article References: Kim, Y.-K., & Kook, H. (2026). Rebalancing the non-coding RNA research agenda: future directions for long non-coding RNA and circular RNA research. Experimental & Molecular Medicine, 58(9), 2809-2811. https://doi.org/10.1038/s12276-026-01832-x

Image Credits: AI Generated

DOI: 10.1038/s12276-026-01832-x

Keywords: lncRNA, circRNA, non-coding RNA, ceRNA hypothesis, RNA structure, RNA biogenesis, quantitative biology, isoform identity, Experimental & Molecular Medicine, RNA therapeutics, Rebalancing, non-coding