Atrial fibrillation (AF) care has shifted dramatically, with a focus on early rhythm control to reduce AF-related morbidity and mortality and improve quality of life. However, clinical trials for AF rely on historical definitions of treatment failure, including freedom from recurrence of ≥ 30 seconds of atrial fibrillation/flutter/tachycardia, which is a poor predictor of AF severity, or traditional clinical endpoints (i.e., stroke, heart failure, death) which have low incidence in contemporary AF populations. Therefore, a directly measurable and clinically meaningful measure for these clinical endpoints has the potential to accelerate clinical trials of rhythm control in AF while reducing overall trial overhead. The Cardiovascular Sciences Research Consortium hosted a Think Tank comprising scientists, clinicians, regulators, and industry representatives to develop a roadmap to establish AF burden as a valid surrogate clinical endpoint. This document reviews currently available data to support the use of AF burden as a surrogate endpoint, provides standards for measuring AF burden across measurement modalities and devices, and establishes a practical roadmap for a collaborative approach to validating the use of AF burden. Moving beyond historical definitions of AF treatment success and failure, AF burden has the potential to be a patient-centric endpoint that can leverage contemporary monitoring technologies while serving as an early signifier of AF-related risk.
Cardiovascular disease (CVD) and cancer are the two leading health issues in the world, with CVD being the leading cause of death in all age groups and cancer, particularly prostate cancer (PCa), emerging as a significant concern among elderly men. Common risk factors like metabolic disorders, chronic inflammatory diseases, and hormone abnormalities have been theorized to be responsible for the increasing prevalence of these diseases. In this study, we examined the relationship between CVD and PCa, with emphasis on the pathophysiological events that connect them and how their coexistence affects patient outcomes. Common PCa treatments, such as androgen deprivation therapy (ADT) as well as androgen receptor signaling inhibitors (ARSI), have been linked to higher rates of hypertension, myocardial infarction, arrhythmias, and metabolic abnormalities. These cardiovascular side effects complicate the effective management of PCa, resulting in poorer overall results. It is essential to implement new integrated approaches to tackle these comorbid conditions. Recommendations include changes in lifestyle, personalized treatment plans, multidisciplinary collaborative efforts, and routine cardiovascular examinations for patients on PCa treatment. Evidence found that personalized exercise regimens and pharmaceutical treatments like statins and antihypertensives may lower cardiovascular risks and enhance outcomes in patients undergoing PCa treatment. Also, emerging technological interventions like wearable devices and telemedicine, such as smartwatches and mobile ambulatory blood pressure monitors (ABPMs), offer real-time cardiovascular monitoring and improve health outcomes among these patients. This study identifies the substantial gaps in clinical guidelines, notably in cardio-oncology integration, and emphasizes the importance of further research into biomarkers, shared inflammatory pathways, and individualized therapy methods. Hence, addressing these gaps will enable a more comprehensive approach to patient care, improving their quality of life and survival.
Cardiovascular disease (CVD) remains the leading cause of mortality worldwide, largely driven by modifiable cardiometabolic risk factors. Adults with metabolic syndrome (MetS) represent a particularly high cardiometabolic risk group in whom preventive strategies are crucial; however, their level of knowledge regarding CVD, its risk factors, and related lifestyle behaviours remains insufficiently characterized. This study aimed to assess the knowledge of CVD and its risk factors among adults with MetS and to examine their associations with lifestyle behaviors and metabolic control. In this single-center cross-sectional study, 350 adults with MetS diagnosed according to ATP III criteria were evaluated. Cardiovascular knowledge was assessed using the validated Cardiovascular Disease Risk Factors Knowledge Level (CARRF-KL) scale. Lifestyle behaviors, anthropometric measurements, laboratory parameters, and medication use were recorded. Associations between CARRF-KL scores and patient characteristics, lifestyle behaviours, and metabolic control were examined. The mean age of the study population was 45.7 ± 11.5 years, and 72% were female. The mean total CARRF-KL score was 21 ± 3, with 42% of participants demonstrating high knowledge levels (≥80% correct responses). Despite this, adherence to lifestyle recommendations was suboptimal, with only 6% reporting regular physical activity and 26% adhering to dietary recommendations. Notably, only 9% of participants were aware of their MetS diagnosis. Higher knowledge scores were associated with higher educational level, better dietary adherence, and lipid-lowering therapy use (p < 0.05), as well as lower rates of smoking and alcohol consumption. However, no significant associations were observed with physical activity or weight-related measures. Although adults with MetS demonstrated moderate to high awareness of CVD and its risk factors, this knowledge did not consistently translate into healthier lifestyle behaviors. Prevention strategies targeting high cardiometabolic-risk populations should extend beyond information dissemination and incorporate behavioral and motivational components to improve cardiovascular outcomes.
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Long coronavirus disease 2019 (COVID-19), or post-acute sequelae of severe acute respiratory syndrome coronavirus 2(SARS-CoV-2) infection, has emerged as a major global health concern. Its relationship with noncommunicable diseases (NCDs) remains underexplored despite overlapping pathophysiological pathways. This bibliometric analysis evaluates global research trends, key contributors, and thematic clusters at the intersection of long COVID-19 and NCDs. A comprehensive search was conducted in Scopus and Web of Science databases using relevant MeSH and/or keyword combinations. Bibliometric indicators including publication trends, prolific authors and country collaboration networks analyzed using VOSviewer and R Bibliometrix. Fifty-five relevant publications were identified between 2020 and 2024. Research activity peaked in 2023, dominated by studies on cardiovascular, metabolic, and respiratory comorbidities. Collaboration networks showed strong contributions from China, the United States, and the United Kingdom. However, limited representation was observed from low- and middle-income countries (LMICs). This bibliometric analysis highlights a growing but uneven global research landscape linking long COVID-19 and NCDs. Cardiovascular and metabolic disorders have received significant attention, whereas neurological and oncological sequelae remain underinvestigated. Future research must strengthen interdisciplinary collaboration and address the inequitable participation of LMICs.
Long-term effect of COVID-19 (Long COVID) may persist for months or years after SARS-CoV-2 infection, but longer-term cardiopulmonary manifestations have not been previously reported. The objective of the study was to characterize cardiopulmonary function after SARS-CoV-2 infection in a digital health substudy of the nationwide Researching COVID-19 to Enhance Recovery Adult Cohort Study. Associations between wearable sensor device measures of cardiopulmonary fitness and survey-derived Long COVID symptoms were estimated over a 6-month window at least 6 months after infection using linear regression models adjusted for wear time, age, sex, race/ethnicity, and body mass index. Among 1,475 participants (72% female, 65% non-Hispanic White) a median of 21 months (IQR: 15-31 months) after infection, 498 (34%) had high symptom burden as characterized by the Researching COVID-19 to Enhance Recovery Long COVID Research Index (LCRI). High LCRI (vs low LCRI) was associated with significantly lower heart rate variability (-4.4 ms; 95% CI: -6.5 to -2.4; P < 0.001), higher resting heart rate (+1.5 beats/min [+0.7 to +2.4]; P < 0.001), fewer metabolic equivalent of task minutes (-96.3 [-128.8 to -63.8]; P < 0.001), lower step counts (-1,624 steps/day [-1,952 to -1,296]; P < 0.001), and lower activity levels (-7.9 minutes/day very or fairly active [-10.9 to -5.0]; P < 0.001). Hierarchal clustering analysis identified two subphenotypes with abnormal cardiovascular measures associated with low quality of life scores. Long COVID is associated with worse cardiovascular fitness. Additional studies are needed to determine if Long COVID is a novel risk factor for incident cardiovascular disease.
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Cardiovascular disease (CVD) accounts for a third of all deaths, making it the leading cause of mortality globally. Coronary microvascular dysfunction (CMD) has emerged as a prominent condition in menopausal women, leading to the development of chronic coronary syndrome (CCS). Despite the significant impact on this cohort, research gaps persist which can lead to shortcomings in the delivery of care to women. CMD is more prevalent in women than men and is linked to increased risk of major adverse cardiovascular events and mortality. During the menopausal transition, there is an acceleration in vascular ageing due to hormonal shift and metabolic changes, resulting in endothelial dysfunction. A large proportion of patients with Takotsubo syndrome and heart failure with preserved ejection fraction (HFpEF) are menopausal women with CMD; however, the underlying mechanisms are not fully understood. Limited evidence of the sex-specific pathophysiology of CMD has resulted in current clinical practice relying on evidence from male-dominant or mixed cohorts. This can lead to incorrect risk stratification, treatment side effects and poor prognosis in women. In addition, there is limited research on the efficacy of diagnostic techniques addressing the sex differences in those with CMD. Tailored diagnostic thresholds and models are essential to improve prognosis in women. Further evidence is needed to bridge these knowledge gaps to tackle the sex differences, achieve sex equality in CVD research and reduce the disproportionate burden of microvascular dysfunction in menopausal women.
Obesity and chronic kidney disease (CKD) are highly prevalent conditions with substantial public health impacts; their co-existence is common and associated with an aggravated risk for adverse outcomes. We conducted an updated systematic review and meta-analysis to evaluate the effects of weight-loss interventions on kidney, cardiometabolic and anthropometric outcomes in overweight or obese adults with CKD. Systematic searches in PubMed, CENTRAL and Embase databases were performed up to August 2025. Randomised-controlled trials evaluating the effects of any weight-loss interventions (lifestyle, pharmacological, surgical approaches) in overweight or obese patients with any stage of CKD were included. Primary endpoints were kidney and cardiovascular outcomes and mortality; secondary endpoints included anthropometric parameters and blood pressure (BP). Forty-two studies (n = 11 017) were included in qualitative and 27 (n = 7015) in quantitative analysis. Cardiovascular outcomes and mortality data were lacking. The estimated glomerular filtration rate (eGFR) demonstrated a non-significant upward trend following lifestyle and pharmacological interventions (incretin-based therapies) and a significant increase following bariatric surgery (MD: 6.09 mL/min/1.73 m2;95% CI: [3.66, 8.52], I2 = 1%). Incretin-based therapies achieved a 41% reduction in urine albumin-to-creatinine ratio compared with placebo (95% CI: [29%, 52%], I2 = 86%). Anthropometric parameters, including weight, body-mass index and waist circumference, improved across all intervention categories, with lifestyle-based approaches most extensively studied (weight-loss MD: -4.13 kg; 95% CI:[-6.49, -1.76], I2 = 83%). Systolic and diastolic BP showed modest, non-significant reductions following lifestyle interventions (SBP MD: -3.10 mm Hg; 95% CI: [-7.59, 1.38], I2 = 45%), while data for pharmacological and surgical approaches were limited and definitive conclusions cannot be made. In CKD patients with overweight or obesity, all types of interventions (lifestyle, pharmacological, surgical) are effective for weight-loss. Incretin-based therapies confer additional nephroprotective effects by significantly reducing albuminuria. Uncertainty persists for the remaining outcomes, highlighting the need for additional research.
Adequate renal perfusion is critical for maintaining kidney function, and its impairment contributes significantly to acute kidney injury (AKI) and related cardiovascular complications. Dopamine (DA) is clinically employed to improve renal perfusion, but its efficacy remains controversial due to paradoxical vasoconstriction at higher doses. This study systematically evaluates DA-induced vasomotor responses in human intrarenal arteries and elucidates the underlying molecular mechanisms. Human intrarenal artery segments, including interlobar (IA, ∼1 mm), arcuate (AA, ∼500 μm), and interlobular arteries (ILA, ∼200 μm), were analyzed using ex vivo tension assays, pharmacological interventions, RNA sequencing, and siRNA silencing to delineate segment-specific DA responses and molecular basis. DA (1 nM-10 µM) consistently induces vasodilation across all human intrarenal arteries, challenging the conventional notion that "renal-dose DA" causes vasoconstriction. IA and AA segments exhibit more pronounced vasodilation than ILA, mediated by dopamine receptor D1 (DRD1)-dependent protein kinase A (PKA)-BK channel signaling. Specifically, higher expression and activity of the BK channel regulatory β-subunit (KCNMB1) in IA and AA accounted for their increased sensitivity to DA. Transcriptomic profiling further identified distinct molecular heterogeneity among IA, AA and ILA segments, reflecting their divergent physiological roles. In contrast, rodent intrarenal arteries respond to DA with vasoconstriction rather than dilation, due to the lack of the BK channel pore-forming α-subunit (KCNMA1), which shifts the balance toward α-adrenergic vasoconstriction. Our study overturns the traditional paradigm of "renal-dose DA"-induced vasoconstriction, supports DRD1 agonism as a promising strategy for renal hypoperfusion, and emphasizes critical species differences that necessitate human-based validation in translational vascular research.
The effects of renin-angiotensin-aldosterone system (RAAS) inhibitors on proteomic biomarkers of cardiovascular disease in dogs remain poorly characterized. To evaluate the effect of RAAS activation and treatment with a combination of benazepril and spironolactone on circulating proteomic biomarkers in healthy dogs. Eighteen healthy beagle dogs. Prospective experimental study. Dogs were fed a low-sodium diet to induce RAAS activation and randomly assigned to 1 of 3 dosing regimens for 14 days: (1) benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q24h (label dose); (2) benazepril 0.25 mg/kg + spironolactone 2 mg/kg PO q12h; or (3) benazepril 0.5 mg/kg + spironolactone 4 mg/kg PO q12h. Plasma samples were collected at multiple time points, and the concentrations of 177 unique proteins were quantified using multiplexed proximity extension assay technology via the Olink Target 96 Inflammation and Cardiovascular II panels. Differences between sampling days and groups were assessed using linear mixed models. Renin-angiotensin-aldosterone system activation was associated with downregulation of proteins associated with cardioprotection, adaptive immunity, and tissue repair (eg, ACE2, FGF-5, CCL4, and MMP-10; P < .05 for all comparisons). Treatment with benazepril and spironolactone led to upregulation of adaptive immune proteins (eg, CCL4, TSLP) and proteins with cardioprotective functions (eg, ACE2). Dose-related differences were observed for a subset of biomarkers. In this experimental model of RAAS activation, benazepril/spironolactone combination therapy exerts effects on markers of inflammation and fibrosis in dogs.
Cardiac fibrosis is one of the main causes of mortality from cardiovascular disorders and may result in heart failure, irregular heartbeats, and sudden cardiac death. Multiple complex mechanisms involved in cardiac fibrosis are beyond the scope of current treatments. Inflammasomes are significant inflammatory modulators. Inflammasome impairment may exacerbate heart failure. The most specific inflammasome associated with inflammatory and cardiovascular disorders is Nucleotide-binding oligomerisation domain leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3). Pathogen-associated molecular patterns and damage-associated patterns are recognised by the intracellular sensor NLRP3, which causes the NLRP3 inflammasome to assemble and become active. Thus, a greater awareness of the pathological function of the inflammasome in heart fibrosis may lead to new approaches to the disease's early detection and management. Understanding the inflammasome's regulatory functions in fibrosis of the heart in its entire form has been made possible by recent research on the subject. The most recent studies on the roles of the NLRP3 inflammasome in different cardiac conditions are included in this review. According to recent research, the NLRP3 inflammasome promotes a number of inflammatory reactions and is linked to myofibroblast development, mitochondrial modulation, and pyroptosis in cardiac fibrosis. These discoveries provide light on the critical function of the NLRP3 inflammasome in the aetiology of heart fibrosis, which may help establish novel paths for therapy and prevention.
This study aims to map the application landscape, core technical components, key challenges, and future directions of digital twin technology in medical diagnosis through a scoping review and bibliometric analysis. Following PRISMA-ScR and BIBLIO guidelines, we searched five databases from inception to July 16, 2025, identifying 64 eligible studies. We analyzed data on research landscape (national output, collaboration, funding, interdisciplinarity), technical components (data sources, modeling), model maturity, and application scenarios. Global output was concentrated in the United States (19.4%), the United Kingdom (10.9%), and China (10.1%), which formed the core hubs of international collaboration. Funding was primarily from government (40.4%) and nonprofit organizations (26.6%). The field is AI-centric and notably interdisciplinary. Diagnostic digital twins commonly adopt hybrid modeling that combines physics-based simulation with data-driven analytics. Medical imaging was the dominant data source (70.3%), and deep learning served as the principal algorithmic driver. Overall technological maturity remained low: most models (97%) were at L2-Conception and L3-Operations, while systems with real-time, closed-loop feedback (L4) were rare. Current applications focus on automated lesion detection, individualized risk stratification, and dynamic monitoring/diagnostics, with promising accuracy in cardiovascular diseases, oncology, and neurologic disorders. Digital twins are a key enabling technology for predictive, personalized, and systemic precision diagnostics. Translation faces data scarcity, model computational burden, insufficient validation, limited interpretability, workflow integration, and regulatory gaps. Future work should prioritize multi-center data federations, efficient and trustworthy hybrid modeling, large-scale clinical validation, and adaptive regulatory frameworks to accelerate clinical adoption.
Studying the genetic basis of human phenotypes involves two primary strategies. Model-system experiments generate interpretable gene networks but do not establish relevance to human disease. In contrast, statistical genetics identifies variant- and gene-level associations but cannot test mechanistic models. Here, we bridge these approaches by introducing NERINE, a hierarchical model-based rare variant association test that incorporates gene network topology while remaining robust to network inaccuracies. NERINE supports analysis of networks from established pathway databases and model-system screens. A comprehensive search across pathway databases reveals associations for breast cancer, cardiovascular diseases, and type 2 diabetes not detected by single-gene tests. Applied to experimental screen-derived networks in Parkinson's disease (PD), NERINE highlights autophagy-, vesicle-trafficking-, and protein-homeostasis-related gene modules. Genome-scale CRISPR interference (CRISPRi) screening in human neurons and NERINE converge on PRL, revealing an intraneuronal α-synuclein/prolactin stress response that may impact resilience to PD.
Exposure to space radiation represents a critical issue for astronauts' health, since it can lead to different types of effects including cancer, cataract, skin damage, damage to blood forming organs, cardiovascular diseases, CNS damage etc. Space radiation exposure is characterized by relatively low dose rates over long periods due to Galactic Cosmic Rays, plus short, higher-dose exposures in case of intense Solar Particle Events (SPE). In this framework the BIANCA biophysical model, which until now has been applied to predict cell death and chromosomal aberrations following acute exposure, was extended by integrating the Lea-Catcheside approach, which takes into account the effects of dose fractionation and dose rate; the good agreement between model predictions and proton cell survival data on fractionated irradiation (either obtained in this work, or taken from the literature) allowed validating the model for the considered scenarios. Afterwards, exploiting an interface with the FLUKA radiation transport code, BIANCA was applied to analyze the impact of dose rate for the August 1972 SPE, by calculating RBE-weighted organ doses in a human voxel phantom under different shielding conditions and for different irradiation durations. The results showed differences up to 50 % in the RBE-weighted dose between acute and protracted irradiation; such difference tends to decrease with increasing shielding. Following this work, BIANCA can now predict RBE values for cell survival taking into account not only the RBE dependence on particle type, energy and dose, but also the dependence on dose-rate. This allowed improving the accuracy in the prediction of astronauts' Gy-equivalent doses in case of a SPE exposure.
This cross-sectional study compared basal and exercise-induced cholesterol transfer to HDL and related metabolic markers in young (n = 7) and master (n = 12) endurance-trained athletes performing a standardized 30-min moderate-intensity cycling bout. Despite similar lipid profiles, exercise intensity, and metabolic load in both groups, only master athletes showed a significant post-exercise increase in esterified cholesterol transfer to HDL (p = 0.012), whereas HDL-C remained unchanged. These findings suggest that lifelong endurance training may preserve specific aspects of HDL functionality across ageing, even in the absence of differences in conventional lipid measures, with potential relevance for cardiovascular protection.
Residual cardiovascular risk remains high after acute coronary syndrome (ACS) despite intensive LDL-cholesterol lowering. Elevated triglycerides may contribute to this risk. Although icosapent ethyl (IPE) has shown cardiovascular benefit in high-risk statin-treated patients, access in Italy is limited by Italian Medicines Agency (AIFA) reimbursement criteria, which are more restrictive than the European Medicines Agency (EMA) indications. We compared EMA and AIFA eligibility for IPE in a real-world post-ACS cohort, assessed the association of triglyceride levels and variability with 12-month ischemic recurrence, and explored the potential economic impact of broader IPE use. This retrospective observational study included 430 consecutive adults admitted for ACS to a tertiary hospital in Italy in 2024, with 12-month follow-up. During follow-up, 48 patients (11.2%) experienced recurrent ACS. Diabetes mellitus was independently associated with recurrence (OR 2.90, 95% CI 1.41-5.97; p = 0.004), whereas male sex was protective (OR 0.46, 95% CI 0.23-0.93; p = 0.030). Absolute triglyceride levels were not significantly associated with recurrence, whereas triglyceride variability was: the coefficient of variation remained independently associated with recurrent events (OR 1.04, 95% CI 1.00-1.09; p = 0.029). According to EMA criteria, 35 patients (8.1%) were eligible at discharge and 15 (3.5%) at first follow-up; under AIFA criteria, only one patient was eligible. A marked discrepancy exists between EMA indications and AIFA reimbursement criteria for IPE, resulting in restricted access for high-risk post-ACS patients. Broader access, aligned with current evidence, may improve secondary prevention and represent a cost-effective strategy.
To compare influenza-related hospitalisation, mortality and effects of background factors in adults with type 2 diabetes (T2D) and age-matched and sex-matched controls. To explore associations between clinical variables and the risk of severe influenza outcomes. Register-based nationwide cohort study. Data from the National Diabetes Register are cross-linked to the Swedish Population Register, Statistics Sweden and the Swedish Patient Register. 371 811 patients with T2D from the Swedish National Diabetes Register and 1 728 856 matched control individuals from the Swedish population followed over the 2013/14-2018/19 influenza seasons. Data on hospital admissions, mortality, socioeconomic factors and pre-existing conditions were collected. Risk associations were analysed using Cox proportional hazards models. Within the diabetes group, non-linear associations between common clinical variables and influenza hospitalisation were examined. 1.6% of those with diabetes and 1.0% of controls were hospitalised for influenza, with influenza-related mortality at 0.12% and 0.08% respectively. Adjusted HR for hospitalisation in T2D was 1.57 (95% CI 1.52 to 1.61) and 1.44 (95% CI 1.29 to 1.61) for mortality. Absolute risk was highest in those with cardiovascular, kidney or respiratory disease. Relative risk was greatest in younger (<65 years) patients with T2D. Higher haemoglobin A1c (HbA1c) and lower estimated glomerular filtration rate (eGFR) were linked to increased hospitalisation risk in persons with T2D. This study confirms that T2D increases the risk of hospitalisation and mortality from seasonal influenza. Support to achieve HbA1c and eGFR targets and following vaccination guidelines is important.
The impact of mercury (Hg) on the estimated glomerular filtration rate (eGFR) remains inconsistent across epidemiological studies, often due to low exposure levels or the presence of dietary factors such as selenium (Se). This study evaluates the independent association between blood Hg and eGFR in a population with high dietary fish intake. A cross-sectional study was conducted on 373 healthcare workers in Madrid, Spain. Blood levels of Hg were measured by cold vapour atomic absorption spectrometry and Cd, Pb and Se by electrothermal atomization atomic absorption spectrometry. eGFR was calculated using the CKD-EPI formula. Participants were categorized by the median blood Hg level (8 µg/L), a threshold previously linked to cardiovascular risk. Participants had a mean age of 47.3 ± 10.9 years, and a mean estimated glomerular filtration rate (eGFR) of 78.9 ± 11.8 mL/min/1.73 m²; 16.1% were male. Median blood mercury concentration was 8.0 µg/L (IQR: 5.2-11.6); median cadmium and lead levels were 0.29 µg/L (IQR: 0.18-0.50) and 1.7 µg/dL (IQR: 1.0-2.8), respectively, while mean selenium was 79.4 ± 11.7 µg/L. In linear regression analyses, blood mercury levels > 8 µg/L were associated with lower eGFR in the unadjusted model (β = -3.78; 95% CI: -6.17 to -1.39; p = 0.002) and after adjustment for age, sex, and vascular risk factors (β = -3.08; 95% CI: -5.45 to -0.72; p = 0.011). This association remained significant after further adjustment for co-exposure to cadmium, lead and selenium (β = -2.62; 95% CI: -5.02 to -0.21; p = 0.033). In a population of healthcare workers with high fish consumption, blood mercury levels above 8 µg/L are associated with a modest reduction in eGFR. These findings suggest that Hg may exert a subtle influence on renal filtration independent of other common nephrotoxic metals and dietary elements like selenium.
Oral cavity squamous cell carcinoma (OCSCC) driven by areca nut consumption-a Group 1 carcinogen affecting 600 million people globally-represents a significant unmet need in precision prevention. Despite the known role of COX-2-mediated inflammation in this etiologic niche, pharmacological strategies remain under-evaluated. We emulated a target trial using a nationwide matched cohort of 50,606 areca nut chewers from the Taiwan National Health Insurance Research Database (2008 to 2021). To minimize selection and immortal time biases, we utilized time-dependent exposure modeling and Fine-Gray subdistribution hazard models to account for competing mortality. Aspirin initiation was associated with a significantly lower risk of incident OCSCC (adjusted sHR, 0.75; 95% CI, 0.65-0.87; P<.001). We identified a robust dose-response relationship, with a 43% risk reduction observed in the high-cumulative-exposure group (≥ median cDDD; sHR, 0.57; 95% CI, 0.47-0.69). The exploratory estimated 5-year number needed to treat (NNT) was 249 for the high-dose group. Sensitivity analyses, including E-value assessment (2.89) and landmark tracking, confirmed the stability of this association against unmeasured confounding and reverse causality. Our findings provide large-scale human evidence that sustained aspirin use significantly alters the trajectory of oral field cancerization in areca nut chewers. This study identifies aspirin as a high-priority candidate for risk-stratified chemoprevention in global populations with high areca nut exposure.