Non-coding RNAs emerge as diagnostic and therapeutic leads in abdominal aortic aneurysm

Abdominal aortic aneurysm, a permanent dilation of the body’s largest artery that develops silently over years and can kill within minutes if it ruptures, is the focus of a new review that maps an entire layer of gene regulation previously invisible to vascular surgeons. Writing in Molecular Biology Reports, a team from Pomeranian Medical University in Szczecin, Poland, led by Patryk Skórka and Andrzej Pawlik, surveys the role of non-coding RNAs in the disease and argues that these molecules could eventually serve both as blood-based warning signals and as drug targets for a condition that currently has no approved pharmacological treatment.

The clinical problem is stark. Abdominal aortic aneurysms are progressive and often asymptomatic, so most are discovered incidentally during imaging for other complaints. Diagnosis today relies on ultrasonography and computed tomography, which measure the diameter of the vessel but reveal little about the biological activity inside its wall. Rupture carries a high mortality rate, and the only interventions that change the disease course are surveillance and surgical repair once the aneurysm reaches a size threshold. Molecular biomarkers, the review’s authors note, may add information about disease activity that diameter alone cannot provide, and non-coding RNAs are emerging as some of the most promising candidates.

Non-coding RNAs are RNA molecules that are transcribed from the genome but not translated into proteins, and they have moved from being dismissed as transcriptional noise to being recognized as master regulators of gene expression. The review organizes them into three main classes. MicroRNAs are short molecules that bind to target messenger RNAs and primarily suppress translation or promote the degradation of those messages. Long non-coding RNAs are longer transcripts that can regulate genes through multiple mechanisms, including chromatin modification and transcriptional control. Circular RNAs are covalently closed loops that are exceptionally stable, and some of them act as sponges that sequester microRNAs, reducing the pool available to silence their targets. Together these classes form a dense regulatory network whose perturbation appears to sit at the heart of aneurysm pathology.

What makes the review distinctive is its insistence on separating evidence by the strength of the system in which it was generated. The authors distinguish human tissue and circulating studies from animal, cellular, and purely computational findings, a hierarchy that matters enormously when deciding which molecules deserve clinical attention. Particular emphasis falls on a handful of candidates with functional experimental evidence or human biomarker data beyond simple expression profiling: the microRNA miR-21, the long non-coding RNAs H19 and GAS5, the circular RNA circCdyl, and miR-26b-3p.

MiR-21 has one of the most striking stories in the field. Work published in Science Translational Medicine by Maegdefessel and colleagues showed that microRNA-21 blocks abdominal aortic aneurysm development and suppresses the nicotine-augmented expansion of aneurysms in experimental models, positioning it as a protective rather than a pathogenic factor. H19, by contrast, appears to drive disease. Li and colleagues reported in Circulation that H19 induces abdominal aortic aneurysm development and progression, and a companion study in the Journal of Molecular and Cellular Cardiology showed that H19 promotes vascular inflammation and aneurysm formation by functioning as a competing endogenous RNA, effectively soaking up microRNAs that would otherwise restrain inflammatory pathways. GAS5, meanwhile, has been implicated in the death of vascular smooth muscle cells: He and colleagues demonstrated in Theranostics that GAS5 induces aneurysm formation by promoting smooth muscle apoptosis, and follow-up work showed that knocking down GAS5 reduces that apoptosis by inactivating an EZH2-mediated RIG-I signaling pathway.

The circular RNA candidates add a further dimension. Song and colleagues reported in Molecular Therapy that circular RNA Cdyl promotes aneurysm formation by inducing M1 macrophage polarization and the M1-type inflammation that accompanies it, implicating immune cells rather than only the vessel wall itself. On the protective side, He and colleagues showed in Molecular Therapy Nucleic Acids that circular RNA Chordc1 protects mice from aneurysm by contributing to the phenotype and growth of vascular smooth muscle cells, the cells that normally maintain the elastic integrity of the aorta. Guo and colleagues, publishing in Circulation, uncovered a different layer of regulation entirely: LXRα promotes aneurysm formation through epigenetic modification of miR-26b-3p, linking lipid-sensing transcription factors, epigenetics, and microRNA biology in a single pathogenic axis.

These findings converge on the central cellular process in aneurysm disease: the phenotypic switching of vascular smooth muscle cells. In a healthy aorta, these cells are contractile and maintain the wall’s structural integrity. Under pathological stress they switch to a synthetic, inflammatory, and matrix-degrading state, and they can undergo apoptosis, leaving the wall weakened. Non-coding RNAs regulate nearly every step of this transition. MiR-23b, for example, prevents aneurysm formation by inhibiting smooth muscle cell phenotypic switching through suppression of FoxO4. The lncRNA CARMN inhibits aneurysm formation and smooth muscle transformation by interacting with the transcription factor SRF. MiR-126a-5p limits aneurysm formation in mice by decreasing expression of ADAMTS-4, a matrix-degrading enzyme. MiR-30c-1-3p targets matrix metalloproteinase 9, an enzyme long known to be activated in human aneurysm tissue since the landmark 1996 finding that activated forms of MMP2 and MMP9 are present in aneurysm walls.

Inflammation and immune cell behavior form a second major theme. MiR-144-5p limits experimental aneurysm formation by mitigating M1 macrophage-associated inflammation through suppression of TLR2 and OLR1. The transcription factor TCF3 promotes macrophage-mediated inflammation and matrix metalloproteinase secretion by regulating the miR-143-5p/CCL20 axis. M1 macrophage-derived exosomes carrying the lncRNA PVT1 promote inflammation and pyroptosis, an inflammatory form of cell death, in vascular smooth muscle cells by inhibiting miR-186-5p and regulating HMGB1. Oxidative stress adds yet another layer: miR-192-5p, a downstream effector of NADPH oxidases, reverses endothelial dihydrofolate reductase deficiency and attenuates aneurysm formation, while miR-199a-5p aggravates aneurysm by targeting Sirtuin-1 and driving smooth muscle cell senescence. The circular RNA Ataxia Telangiectasia Mutated regulates oxidative stress in smooth muscle cells in expanding aneurysms, and silencing the lncRNA Sox2ot inhibits oxidative stress and inflammation through a microRNA-145-mediated pathway.

On the diagnostic side, the review highlights circulating non-coding RNAs detectable in peripheral blood, which would allow repeated, minimally invasive sampling. A 2023 study in the European Journal of Vascular and Endovascular Surgery associated serum microRNAs with aneurysm diagnosis and growth. Serum miR-1-3p has been proposed as a potential circulating biomarker. Let-7f was identified as a new potential circulating biomarker through microRNA profiling of cells isolated from human aneurysm tissue. Patients with aneurysms have reduced levels of microRNA 122-5p in circulating exosomes, the small membrane vesicles that cells release into the bloodstream. Postoperative serum miR-28-5p levels have shown predictive value for prognosis after endovascular aneurysm repair, and next-generation sequencing of microRNAs in small aneurysms identified miR-24 as a candidate biomarker. Whole-blood expression of miRNA-191 and miRNA-455-3p has been linked to clinical outcomes after endovascular repair. These are early findings, and the review is careful to note that abnormal expression detected in blood or aortic tissue does not necessarily predict aneurysm growth or rupture.

The therapeutic implications are equally provocative but further from the clinic. Inhibition of microRNA-33b has been shown to ameliorate aneurysm formation specifically through suppression of inflammatory pathways. Galactose-modified nanoparticles have been used to deliver microRNA to macrophages, mitigating aneurysm progression by regulating macrophage polarization, an early proof of concept for targeted RNA delivery to the diseased vessel wall. The review argues that integrating non-coding RNA profiling with imaging and clinical parameters may improve assessment of aneurysm activity beyond diameter alone. But the authors are equally clear about the barriers: prospective validation in large cohorts, deeper studies of delivery methods, and safety data are all needed before any of these molecules can enter clinical practice. For now, the molecular landscape of abdominal aortic aneurysm is being charted one RNA at a time, and the map is growing faster than the tools to navigate it.

Subject of Research: The role of non-coding RNAs as diagnostic biomarkers and therapeutic targets in abdominal aortic aneurysm

Article Title: The emerging molecular landscape of abdominal aortic aneurysms: non-coding RNAs as diagnostic and therapeutic targets

Article References: Skórka, P., Brelik, J., Kiełbowski, K., Dorsz, D., Szulc, J., Bakinowska, E., Rynio, P., & Pawlik, A. (2026). The emerging molecular landscape of abdominal aortic aneurysms: non-coding RNAs as diagnostic and therapeutic targets. Molecular Biology Reports, 53(1), Article 1752. https://doi.org/10.1007/s11033-026-12947-9

Image Credits: AI Generated

DOI: 10.1007/s11033-026-12947-9

Keywords: abdominal aortic aneurysm, non-coding RNA, microRNA, long non-coding RNA, circular RNA, biomarkers, vascular smooth muscle cells, inflammation, molecular therapy, gene regulation, aortic rupture, RNA therapeutics