Functional role of circular RNA XYLT1 in vascular remodeling and oxidative stress in aging

Neointimal hyperplasia represents a fundamental pathological process in the development of atherosclerosis, post-angioplasty restenosis, and aneurysms. It is primarily driven by the excessive proliferation and migration of vascular smooth muscle cells (VSMCs), which contribute to vascular wall thickening and luminal narrowing (Kansakar et al., 2021). Despite the availability of pharmacological and interventional strategies, the recurrence of neointimal hyperplasia remains a significant clinical challenge (Zhang et al., 2025). Thus, understanding the molecular mechanisms governing VSMC behavior is crucial for identifying novel therapeutic targets.

One emerging avenue of research is the role of circular RNAs (circRNAs), a class of non-coding RNAs with significant regulatory functions in cellular processes, including proliferation, apoptosis, and inflammation (Bibi et al., 2025; Ni et al., 2024; Liu et al., 2023; Zhu et al., 2020; Lopez-Jimenez and Andres-Leon, 2021). CircRNAs have gained increasing attention in cardiovascular research due to their stability and ability to act as microRNA sponges, protein decoys, or transcriptional regulators (Mu et al., 2025; Zhang et al., 2020). Among these, CircXYLT1 has emerged as a novel modulator of oxidative stress, inflammation, and vascular remodeling. In this issue of Experimental Gerontology, Gang Li and collaborators (Li et al., 2025) are showing that CircXYLT1 suppresses oxidative stress and promotes vascular remodeling through its interaction with the RNA-binding protein PTBP1, thereby influencing critical pathways in vascular pathophysiology.

1. CircXYLT1 and oxidative stress: a key player in vascular protection

Oxidative stress is a well-established driver of vascular aging and disease progression (Mone et al., 2023). The accumulation of reactive oxygen species (ROS) leads to endothelial dysfunction, inflammation, and VSMC activation, exacerbating neointimal hyperplasia (Scioli et al., 2020). CircXYLT1 overexpression was shown to reduce oxidative stress in VSMCs by enhancing the activity of key antioxidant enzymes, including superoxide dismutase (SOD), glutathione peroxidase (GPX), and heat shock proteins (HSPs) (Li et al., 2025).

SOD is an essential antioxidant enzyme that catalyzes the dismutation of superoxide anions (O₂•−) into hydrogen peroxide (H₂O₂) and molecular oxygen. By preventing the accumulation of superoxide, SOD protects against peroxynitrite (ONOO⁻) formation, which is highly cytotoxic and contributes to endothelial dysfunction and VSMC proliferation (Fujii et al., 2022). CircXYLT1 overexpression upregulates SOD expression, thereby enhancing ROS scavenging capacity and preserving nitric oxide (NO) bioavailability (Li et al., 2025). NO plays a crucial role in maintaining vascular homeostasis by promoting vasodilation and inhibiting VSMC proliferation (Gambardella et al., 2020). The ability of CircXYLT1 to modulate SOD levels suggests that it may exert protective effects against oxidative stress-induced vascular remodeling, highlighting its potential as a therapeutic target.

Glutathione peroxidases (GPXs) are another class of antioxidant enzymes that protect cells from oxidative damage by reducing hydrogen peroxide and lipid hydroperoxides. GPX-1, which is widely expressed in vascular tissues, plays a crucial role in maintaining redox homeostasis and preventing lipid peroxidation—a process that drives atherosclerosis progression (Handy and Loscalzo, 2022). CircXYLT1 significantly upregulates GPX expression, leading to decreased ROS accumulation and lipid peroxidation (Li et al., 2025). Since lipid peroxidation products such as malondialdehyde (MDA) (Tang et al., 2021) contribute to endothelial dysfunction and foam cell formation, the ability of CircXYLT1 to enhance GPX activity suggests a protective role against atherosclerotic plaque development.

Heat shock proteins (HSPs) function as molecular chaperones, maintaining protein homeostasis and protecting cells from stress-induced damage. HSP70, in particular, has been shown to exert anti-inflammatory effects and modulate insulin resistance, linking it to cardiovascular disease prevention (Szyller and Bil-Lula, 2021). Of note, CircXYLT1 enhances HSP expression, thereby promoting cellular resilience against oxidative and inflammatory stressors (Li et al., 2025). This observation is particularly relevant in aging-related vascular diseases, where oxidative damage accumulates over time, accelerating disease progression.

2. CircXYLT1 and inflammation: disrupting a vicious cycle

Inflammation and oxidative stress are intricately linked in the pathogenesis of vascular diseases. Chronic inflammation leads to increased ROS production, while oxidative stress amplifies inflammatory signaling pathways, creating a self-perpetuating cycle that drives neointimal hyperplasia (Mittal et al., 2014). CircXYLT1 modulates inflammatory responses by impairing PTBP1 nuclear localization (Li et al., 2025), thereby downregulating chemokine signaling pathways. Chemokines are small cytokines that regulate immune cell recruitment and activation, playing a key role in vascular inflammation. By suppressing chemokine-mediated signaling, CircXYLT1 reduces the inflammatory burden on VSMCs and endothelial cells, mitigating vascular damage.

3. The PTBP1 axis: a novel regulatory pathway

PTBP1 (Polypyrimidine Tract Binding Protein 1) is an RNA-binding protein involved in mRNA processing, splicing, and stability; emerging evidence suggests that PTBP1 plays a role in regulating cellular proliferation and apoptosis, making it a critical modulator of vascular homeostasis (La Porta et al., 2016). CircXYLT1 interacts with PTBP1 to regulate oxidative stress and inflammation in VSMCs; specifically, CircXYLT1 binding to PTBP1 impairs its nuclear localization, reducing its ability to modulate inflammatory pathways (Li et al., 2025). This novel regulatory mechanism provides insights into how CircXYLT1 controls vascular remodeling and highlights PTBP1 as a potential therapeutic target.

4. Therapeutic implications: targeting CircXYLT1 for cardiovascular disease management

The discovery of CircXYLT1 as a key modulator of oxidative stress and inflammation opens up new therapeutic possibilities for managing age-related vascular diseases. While there is strong preclinical evidence for the role of CircXYLT1 in vascular remodeling, several challenges remain, including mechanistic exploration, translational validation, and delivery strategies. Several appraches could be explored to harness its therapeutic potential: a) CircXYLT1 Overexpression Therapy: Delivering CircXYLT1 mimics or stabilizing its expression could enhance antioxidant defense mechanisms and reduce inflammation, providing a novel approach for treating atherosclerosis and restenosis; b) CircXYLT1-Based Biomarkers: Monitoring CircXYLT1 expression levels in patients could serve as a biomarker for vascular disease progression and treatment response, enabling personalized therapy; c) Targeting the CircXYLT1-PTBP1 Axis: Developing small molecules or RNA-based therapies that modulate the CircXYLT1-PTBP1 interaction could provide a targeted strategy for reducing neointimal hyperplasia and vascular inflammation.

5. Conclusions

CircXYLT1 is a key regulator of oxidative stress and inflammation; by interacting with PTBP1, CircXYLT1 modulates critical pathways that influence VSMC proliferation, neointimal hyperplasia, and vascular remodeling. The ability of CircXYLT1 to enhance antioxidant defenses, reduce inflammation, and protect against oxidative damage highlights its potential as a therapeutic target in atherosclerosis, restenosis, and aneurysms. Further research into the clinical applications of CircXYLT1 could pave the way for novel RNA-based therapies aimed at preserving vascular health and combating cardiovascular diseases in aging populations. As research into circRNAs continues to evolve (Yuan et al., 2024), leveraging their regulatory potential may revolutionize our approach to vascular disease management, bringing us closer to precision medicine in cardiovascular therapeutics.

Data availability

No data was used for the research described in the article.