Redox Dysregulation in the Abdominal Aortic Aneurysm Wall: Ferroptosis and Experimental Therapeutic Opportunities

Q: What is the clinical evidence from this study?

Study design: Review. Population: Abdominal aortic aneurysm (AAA). Intervention: Experimental redox and ferroptosis modulators (iron handling, phospholipid peroxidation, and antioxidant defence interventions). Primary outcome: Vascular smooth muscle cell survival, macrophage recruitment/secretion, matrix integrity, and aortic aneurysm enlargement.

Yi Huang; Feng Zhu; Chuanqi Cai; Dan Shang

doi:10.3390/jcdd13100510

October 10, 2026Journal of Cardiovascular Development and DiseaseOpen Access

Redox Dysregulation in the Abdominal Aortic Aneurysm Wall: Ferroptosis and Experimental Therapeutic Opportunities

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Key result

Targeting ferroptosis pathways modulates vascular cell survival and limits experimental abdominal aortic aneurysm progression.

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Why the study?

No pharmacological treatment has reliably arrested the enlargement of abdominal aortic aneurysm, a spatially heterogeneous disease of the aortic wall.

Key Points

Examine how redox dysregulation, iron handling, and ferroptosis drive vascular wall injury and evaluate experimental therapeutic strategies in abdominal aortic aneurysm.
Narrative review synthesizing findings from human abdominal aortic aneurysm tissue, cultured vascular cells, and animal models identified via PubMed and Web of Science searches through July 2026.
Evaluated mechanisms of iron uptake, ferritin turnover, phospholipid peroxidation, and antioxidant defence across the intraluminal thrombus-wall interface and vascular wall cells.
Global deletion of lipoxygenase genes Alox12 or Alox15 and inhibition of factor Xa reduced aneurysm development in angiotensin II-infused mice, linking oxidised phospholipids to vascular injury.
In cultured human aortic vascular smooth muscle cells, ACSL4 knockdown and ferrostatin-1 suppressed lipid oxidation and death triggered by Fusobacterium nucleatum supernatant or isoleucine.
Extracellular vesicles from PKM2-activated T cells enhanced macrophage iron accumulation, lipid oxidation, and migration, whereas ferrostatin-1, liproxstatin-1, and deferoxamine suppressed migration without increasing cell death.

Structured PICO

P

Population

Human abdominal aortic aneurysm surgical tissue specimens and experimental cellular and animal models (such as Ang II-infused, elastase, and CaCl2 rodent models) reviewed from literature through July 2026.

I

Intervention

Experimental therapeutic manipulation of iron uptake/export and ferritin turnover (e.g., GM3/TFR1, PCSK9/Cadd4, hepcidin), membrane phospholipid peroxidation susceptibility (e.g., ACSL4, Alox12/15, dietary isoleucine restriction), radical-trapping antioxidants (e.g., ferrostatin-1, liproxstatin-1), peroxide detoxification (e.g., GPX4, PRDX2, RvD1, SENP3/CTH), and targeted nanoparticle/vesicle delivery systems

O

Outcome

Vascular smooth muscle cell ferroptotic death and survival, macrophage recruitment and inflammatory/proteolytic secretion, extracellular matrix/elastin degradation, and abdominal aortic aneurysm enlargement or rupture

Limitations

Surgical human AAA specimens mainly represent advanced lesions and cannot be assumed to describe earlier aneurysm growth.
Animal AAA models reproduce different components of human disease and differ anatomically from chronic human intraluminal thrombus and wall remodelling.
Most experimental interventions are initiated before or during aneurysm induction rather than after imaging confirmation of established aneurysm formation.
Current experimental interventions do not separate the contributions of cell survival, recruitment, and secretion to net aortic outcome.
Systemic dosing of redox, iron, or lipid modulators carries unresolved cellular selectivity and potential off-target systemic effects (such as bleeding or blood pressure changes).
Surgical human specimens mainly represent advanced disease stages and may not reflect earlier aneurysm growth.
Animal models do not fully replicate the chronic spatial heterogeneity and endoluminal intraluminal thrombus of human AAA.
Most experimental studies initiate treatment before or at induction without pretreatment imaging confirmation of established aneurysm.
Changes in oxidative markers or reduced aneurysm burden alone do not establish that protection is mediated specifically by preventing ferroptotic cell death.
Cellular selectivity and systemic safety of targeting iron, coagulation lipids, and antioxidant pathways remain unresolved.

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Implication

Distinguishing lethal ferroptosis in vascular smooth muscle cells from non-lethal redox signalling in macrophages and coagulation is essential for designing targeted therapies that arrest established abdominal aortic aneurysm growth without impairing wall maintenance or systemic homeostasis.

Abstract

Abdominal aortic aneurysm (AAA) is a spatially heterogeneous disease of the aortic wall for which no pharmacological treatment has reliably arrested enlargement. The term oxidative stress encompasses processes that differ in chemical form, anatomical location and cellular effect. This narrative review examines haem and redox-active iron, phospholipid peroxidation and antioxidant defence at the intraluminal thrombus-wall interface and within medial and inflammatory cells. We distinguish ferroptosis from redox effects on coagulation, migration and secretion and relate these functions to wall remodelling. Experimental studies show that manipulating iron uptake and ferritin turnover, membrane phospholipid susceptibility or peroxide detoxification can alter vascular smooth muscle cell survival, macrophage behaviour and aortic injury. The cellular function affected helps determine which process an intervention should preserve or suppress. Based on evidence from human tissue and animal models, we review opportunities to localise, manipulate and monitor these processes and assess their relevance to established AAA. Testing after confirmation of aneurysm formation, with target engagement in defined wall cells and parallel assessment of systemic effects, is needed to determine whether these approaches can limit continued enlargement.

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Cite This Study

Huang et al. (2026) conducted a review in Abdominal aortic aneurysm (AAA). Experimental redox and ferroptosis modulators (iron handling, phospholipid peroxidation, and antioxidant defence interventions) was evaluated on Vascular smooth muscle cell survival, macrophage recruitment/secretion, matrix integrity, and aortic aneurysm enlargement. Manipulating iron handling, phospholipid susceptibility, or peroxide detoxification alters vascular smooth muscle cell survival, macrophage behaviour, and experimental abdominal aortic aneurysm injury.

synapsesocial.com/papers/6aee6b6871a759480622091f https://doi.org/10.3390/jcdd13100510

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Redox Dysregulation in the Abdominal Aortic Aneurysm Wall: Ferroptosis and Experimental Therapeutic Opportunities

Figures

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

Redox Dysregulation in the Abdominal Aortic Aneurysm Wall: Ferroptosis and Experimental Therapeutic Opportunities

Figures

Key Points

Structured PICO

Limitations

Ask about this paper

Implication

Abstract

Discussion

Cite This Study

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