Atherosclerosis remains the principal underlying cause of myocardial infarction, ischemic stroke and peripheral artery disease, and its progression reflects a complex interplay between lipid accumulation, endothelial dysfunction, chronic vascular inflammation and maladaptive remodeling of the arterial wall. The Notch signaling pathway, an evolutionarily conserved juxtacrine communication system, has emerged as a central regulator of every cell type implicated in atherogenesis, including endothelial cells, vascular smooth muscle cells, monocytes/macrophages and T lymphocytes. Depending on the receptor–ligand pairing, the hemodynamic context and the cellular compartment involved, Notch signaling can be either atheroprotective or atherogenic, a duality that has complicated efforts to translate mechanistic insight into therapy. This review summarizes current knowledge of the molecular architecture of the Notch pathway in the vasculature, dissects its cell type-specific and stage-specific contributions to atherosclerotic plaque initiation, progression, calcification and destabilization, and critically appraises pharmacological strategies designed to modulate Notch activity, including γ-secretase inhibitors, ligand- and receptor-directed monoclonal antibodies, soluble decoy receptors, microRNA-based approaches and drug repurposing strategies such as statins. Particular attention is paid to the cardiovascular toxicities that have emerged from oncology trials of Notch pathway inhibitors, which illustrate both the pharmacological tractability and the narrow therapeutic window of this pathway. We conclude that Notch-directed therapy for atherosclerosis is mechanistically well justified but will require cell type-selective and context-selective delivery strategies to be clinically viable.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of mortality worldwide, necessitating novel biomarkers and therapeutic targets. Irisin, a myokine derived from FNDC5, has emerged as a molecule of interest owing to its pleiotropic effects, yet its role in cardiovascular health is debated amid conflicting clinical findings and severe measurement challenges. This review synthesizes and critically evaluates the evidence on irisin in ASCVD, examining its molecular mechanisms, potential as a clinical biomarker, and hurdles for therapeutic application. Preclinical evidence has demonstrated that irisin exerts multifaceted cardioprotective effects: it mitigates cellular stress by enhancing mitochondrial quality control and inhibiting apoptosis and pyroptosis; preserves vascular integrity by promoting angiogenesis and preventing pathological remodeling; and enhances the efficacy of regenerative stem cell therapies. Most clinical studies have revealed an inverse correlation between circulating irisin levels and the presence and severity of ASCVD, heart failure, and related inflammatory conditions. However, these studies are predominantly observational and often cross-sectional, frequently with small sample sizes, and paradoxical elevations occur in certain metabolic states and during acute cardiac injury. Critically, the field is hampered by profound measurement inconsistencies, with reported values spanning picograms to micrograms per millilitre, making cross-study comparisons and clinical cutoffs currently impossible. Irisin appears to be an important endogenous factor in cardiovascular health, and preclinical evidence suggests that it is a promising candidate therapeutic target; however, clinical validation is lacking. Standardization of irisin assays remains the critical step required to determine whether irisin can become a reliable clinical biomarker.

Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of morbidity and mortality worldwide, driven by complex interactions among dyslipidemia, chronic inflammation, insulin resistance, endothelial dysfunction, and gut microbiome-derived metabolites. This review synthesizes mechanistic and clinical evidence on non-pharmacological strategies that modulate these pathways and contribute to ASCVD risk reduction. Dietary patterns such as Mediterranean, DASH, and plant-based diets improve lipid metabolism, attenuate inflammation, and enhance endothelial function. Chrononutrition approaches, including time-restricted feeding and structured fasting protocols, influence circadian regulation of glucose and lipid homeostasis. Circadian misalignment—including irregular sleep timing, shift work, and disrupted feeding–fasting cycles—independently contributes to ASCVD through impaired glucose tolerance, dyslipidemia, endothelial dysfunction, and systemic inflammation. Modulation of the gut microbiome, particularly through increased short-chain fatty acid production and reduced TMAO formation, provides additional cardiometabolic benefits. Key nutraceuticals—phytosterols, omega-3 fatty acids, and berberine—demonstrate clinically meaningful effects through micellar competition, inflammation-resolving lipid mediators, and AMPK activation, respectively. When combined with evidence-based pharmacotherapy, these interventions exert synergistic effects on cardiometabolic risk factors. This integrative biomedical framework highlights the importance of combining lifestyle, metabolic, microbiome-targeted, and nutraceutical strategies for comprehensive ASCVD prevention.

Atherosclerosis and cancer are among the leading causes of morbidity and mortality worldwide and are increasingly recognized as biologically interconnected diseases rather than independent pathological conditions. Accumulating evidence indicates that these disorders share a complex molecular landscape characterized by chronic inflammation, oxidative stress, immune dysregulation, metabolic reprogramming, endothelial dysfunction, and age-related cellular alterations. This review integrates current knowledge on the molecular and cellular mechanisms underlying the bidirectional relationship between atherosclerosis and malignancy, with particular emphasis on inflammatory signaling pathways, NLRP3 inflammasome activation, macrophage polarization, clonal hematopoiesis of indeterminate potential (CHIP), cellular senescence, and gut microbiota-mediated immune modulation. We further discuss how these shared mechanisms contribute to disease initiation, progression, and therapeutic responses, highlighting the influence of cardiovascular medications on cancer biology and the cardiovascular toxicities associated with anticancer therapies. By synthesizing emerging evidence from cardiovascular biology, oncology, and immunology, this review proposes a unified molecular framework in which atherosclerosis and cancer represent interconnected manifestations of common pathogenic processes. Recognizing this molecular crosstalk provides new opportunities for the identification of shared biomarkers, improved risk stratification, and the development of mechanism-based therapeutic strategies, thereby advancing precision medicine at the interface of cardiovascular disease and cancer.