A proteomic analysis of carotid plaque tissue identified 15 high-confidence proteins — including antimicrobial peptides and matrix-degrading enzymes — that distinguish vulnerable, stroke-prone plaques from stable ones.
15 high-confidence proteinsAll upregulated in vulnerable plaques, spanning proteolysis, inflammation, metabolism, and lipid pathways — out of 3,267 total proteins profiled
What the researchers found
Out of 3,267 proteins identified in carotid plaque tissue, 15 reached high-confidence significance (q ≤ 0.25) and were all upregulated in vulnerable plaques. These included matrix metalloproteinases (MMP7, MMP9, MMP1), neutrophil-derived proteins (cathelicidin antimicrobial peptide, azurocidin, lactotransferrin, myeloperoxidase), inflammatory regulators (interleukin-1 receptor antagonist, interleukin-4-induced protein), glycolytic enzymes (hexokinase-2 and hexokinase-3), and lipid-handling proteins (lipoprotein-associated phospholipase A2, apolipoprotein B, paraoxonase-1).
An additional 17 exploratory proteins showed nominal significance with at least a 2-fold change, and 366 more proteins reached nominal significance with smaller fold changes.
Why it matters
Stroke remains a leading cause of death and disability, and carotid plaque rupture is a major trigger. Currently, decisions about surgical intervention rely heavily on imaging, which doesn't always capture the molecular instability within a plaque. Identifying protein biomarkers — especially peptides and enzymes actively involved in plaque breakdown — could lead to blood tests or imaging markers that flag high-risk patients before a stroke occurs, enabling earlier and more targeted prevention.
How the study worked
The researchers collected 28 carotid plaque specimens from 27 patients undergoing endarterectomy (surgical plaque removal). Plaques were classified as vulnerable or nonvulnerable (14 each) based on preoperative MRI with vessel wall imaging. Protein profiling was performed using a tandem mass tag-based multiplexing strategy followed by mass spectrometry. Protein levels were normalized, log2-transformed, and compared using two-sample t-tests with correction for multiple testing using the Benjamini-Hochberg method.
What this study cannot tell us
The sample size was relatively small at 28 plaques from 27 patients, which limits statistical power and generalizability. The study was cross-sectional, meaning it cannot establish whether the identified proteins cause plaque instability or are simply associated with it. Vulnerability classification relied on imaging rather than histopathological confirmation. The findings have not yet been validated against actual stroke outcomes, which is acknowledged as the necessary next step.
How to read the evidence
This is a cross-sectional proteomic study with a small sample size (28 specimens). While the mass spectrometry methodology is rigorous and the statistical approach includes multiple-testing correction, the findings are exploratory and have not been validated in independent cohorts or linked to clinical stroke outcomes.
When this study was published
Published in 2026, this is a very recent study using current proteomic technology. The findings represent the latest in plaque vulnerability biomarker research.
The bigger picture
This study adds to the growing body of proteomics research aiming to move beyond imaging-based risk assessment for cardiovascular events. The identification of antimicrobial peptides like cathelicidin in vulnerable plaques connects to broader research on the role of innate immune peptides in atherosclerosis and vascular inflammation. If validated in larger cohorts, these protein signatures could become part of precision medicine approaches to stroke prevention.
Questions still open
- Could any of these 15 proteins — particularly cathelicidin or the MMPs — be detected in blood tests as non-invasive biomarkers for plaque vulnerability?
- Do these proteomic signatures predict actual stroke events when tracked over time in a prospective study?
- Could targeting specific proteins in this signature (such as the matrix metalloproteinases) offer a therapeutic strategy to stabilize vulnerable plaques?
Common questions
What makes a carotid plaque 'vulnerable'?
What role do antimicrobial peptides play in plaque vulnerability?
Read the original research
Proteomic signatures of carotid plaque vulnerability: Proteolysis, inflammation, metabolic reprogramming, and lipid dysregulation.
JVS-vascular science, 7, 100404
Citation
Sandoval, Camilo Polania; Meschia, James F; Prudencio, Mercedes; Gendron, Tania; Jacobs, Christopher; Beegle, Richard D; Sandhu, Sukhwinder J S; Mangalaparthi, Kiran K; Sung, Jaeyun; Zhao, Xiaowei; Nassar, Aziza; Farres, Houssam; Petrucelli, Leonard; Pandey, Akhilesh; Erben, Young. (2026). Proteomic signatures of carotid plaque vulnerability: Proteolysis, inflammation, metabolic reprogramming, and lipid dysregulation.. JVS-vascular science, 7, 100404. https://doi.org/10.1016/j.jvssci.2025.100404