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.

Legumain, an asparaginyl endopeptidase, has emerged as a critical cysteine protease with diverse and complex roles in human health and disease. While traditionally known for its function in endolysosomal protein degradation, a growing body of evidence has revealed its presence in multiple cellular compartments and its involvement in a vast array of pathological processes. This review provides a comprehensive synthesis of the current literature, bridging the often-siloed research in oncology and cardiovascular medicine to present a unified view of legumain’s function. We first detail the multifaceted role of legumain in cancer, where it acts as a driver of tumour proliferation, invasion, and metastasis. We explore its function as a modulator of the tumour microenvironment, particularly its ability to polarise macrophages towards an immunosuppressive phenotype, and discuss its emerging value as a candidate prognostic biomarker and a versatile therapeutic target. Notably, however, therapeutic targeting of legumain remains predominantly at the preclinical stage. Subsequently, we examine its significant contribution to cardiovascular diseases, detailing its mechanistic involvement in promoting atherosclerosis, hypertension, and adverse cardiac remodelling through pathways involving inflammation, extracellular matrix turnover, and immune cell modulation. By synthesising these findings, we highlight the convergent pathological mechanisms, discuss current controversies and methodological limitations—such as the lack of standardised assays—and propose key future directions. This review frames legumain as a biological rheostat and a potentially important node in chronic disease, underscoring its potential as a powerful biomarker and a sophisticated therapeutic target across a broad spectrum of human pathologies.