Editorial: Proteomics in atherosclerosis

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide and continues to impose a substantial burden of morbidity despite therapeutic advances. Ongoing research into its underlying mechanisms and new risk biomarkers is essential to further mitigate this global health challenge. Without new preventive and therapeutic strategies, population aging and the global risk factors such as obesity, diabetes, and sedentary lifestyle are expected to keep ASCVD rates high 1.Traditional risk scores based on age, blood pressure, lipids, smoking, and diabetes do not fully capture individual risk, especially in younger people, women, and different ethnic groups. New approaches using genetics, multi-omics, and machine learning aim to move beyond simple "high/low risk" categories to more precise, prediction models, which requires further biomarker research 2.Even with LDL-cholesterol lowering and guideline-directed therapies, patients often retain a considerable "residual risk" of heart attack, stroke, and cardiovascular death 3. This residual risk is linked to factors such as triglyceride-rich lipoproteins, inflammation, thrombosis, and other pathways not fully addressed by current drugs, which motivates ongoing research for novel biomarkers 4; 5.Long-running prospective community-based initiatives, such as the Framingham Heart Study (FHS, 1948-present) 6 and the Atherosclerosis Risk in Communities Study (ARIC, 1985present) 7, have accordingly updated aims to integrate genetic profiling and multi-omics to identify novel cardiovascular disease risk factors and biomarkers. More recent prospective studies have cohorts of a half-million (UK Biobank, 2003-present) to million (Million Veteran Program, USA, 2011-present) in order to investigate the effects of genetic, lifestyle and environmental factors at large population scale 8; 9. Proteomics has revolutionized the search for biomarkers in atherosclerosis, enabling the identification of protein signatures that reflect disease presence, progression, and risk. By analyzing tissues, blood, and other biological samples, proteomic approaches provide a wideranging molecular view in risk stratification, early diagnosis, and the development of targeted therapies 10; 11.Our call for submissions to Research Topic Proteomics in Atherosclerosis is timely given the recent announcement of the UK Biobank Pharma Proteomics Project Consortium, aiming to establish connections between genetic variants and their corresponding protein products 12.In our topic collection, the paper by Chen et al investigates whether plasma proteomic profiles can predict carotid intima-media thickness (cIMT), using data from 6,136 UK Biobank participants. The study is methodologically robust, offering predictive value of proteomics over traditional risk factors. While the improvement in prediction is modest, the findings pave the way for early vascular disease detection 13.(<45 years) with acute coronary syndrome (ACS) compared to middle-aged and elderly patients. The study focuses on premature ACS, a growing concern due to lifestyle changes. It integrates clinical risk factors with proteomic analysis using the proximity extension assay on the Olink platform, highlighting age-specific biomarker patterns among young patients with ACS. While preliminary, these findings underscore the need for age-specific prevention strategies and biomarker-driven diagnostics 14. The study by Brandes et al demonstrates that specific microRNAs are simultaneously expressed in circulating extracellular vesicles (EVs) and atherosclerotic plaques in patients with carotid artery stenosis. This paired analysis is novel and suggests that circulating EVs reflect plaque development in patients with symptomatic carotid artery stenosis, which can serve as biomarker candidates for detecting the presence of atherosclerotic plaques 19.Circulating apolipoproteins (APOA1, APOE) whose lipid binding and metabolizing functions are consequential to ASCVD risk, were recently discovered to be ADP-ribosylated. Kasai et al 20 provide a behind the scenes view of mass spectrometer acquisition optimizations required to characterize the posttranslational modification (PTM), ADP-ribosylation. The consequences of this PTM on apolipoprotein function and ASCVD risk may entail mechanistic and functional studies on the chemistry of ADP-ribosylated peptides 21.Finally, while proteins are often in the spotlight as potential biomarker or therapeutic targets, the review by Yan et al provides an overview of miRNAs research in the context of coronary heart disease and diabetes in preclinical and clinical settings 22.Overall, the studies in this collection offer important insights into risk stratification, biomarker-guided diagnostics, and therapeutic strategies for ASCVD. Although differences in study design prevent us from identifying common core molecular mechanisms across all articles, several proteins emerge as potential drivers of atherosclerosis progression. These include cytoplasmic protein NCK1 in relation to carotid intima-media thickness; growth differentiation factor 15, osteopontin, and NT-proBNP in patients with acute coronary syndrome; and fetuin-B, apolipoprotein C-III, and cholesteryl ester transfer protein in relation to in-stent restenosis.