Medicinal Plants and Phytochemicals in Cardioprotection—Mechanistic Pathways and Translational Roadmap

Despite major advances in guideline-directed cardiovascular therapy, residual cardiovascular risk persists, partly driven by oxidative stress, chronic inflammation, endothelial dysfunction, and mitochondrial injury not fully addressed by current drugs. Translation of plant-based cardioprotectants is constrained by preparation-dependent variability in extract chemistry (plant part/cultivar/processing and extraction method), low and variable systemic exposure for key actives (notably curcuminoids and many polyphenols), and clinically relevant safety/interaction considerations (e.g., hepatotoxicity reports with concentrated green tea extracts and antiplatelet-related bleeding-risk considerations for some botanicals). We therefore provide a mechanism- and translation-oriented synthesis of evidence for cardioprotective botanicals, chosen for long-standing traditional use and scientific validation with reproducible experimental data and, where available, human studies, including <i>Crataegus monogyna</i>, <i>Allium sativum</i>, <i>Olea europaea</i>, <i>Ginkgo biloba</i>, <i>Leonurus cardiaca</i>, and <i>Melissa officinalis</i>. Across studies, polyphenols (especially flavonoids and phenolic acids) and organosulfur compounds are most consistently associated with cardioprotection, while terpene-derived constituents and secoiridoids contribute mechanistically in plant-specific settings (e.g., <i>Ginkgo</i> and <i>Olea</i>). Predominantly in experimental models, these agents engage redox-adaptive (Nrf2), mitochondrial (mPTP), endothelial, and inflammatory (NF-κB) pathways, with reported reductions in ischemia-reperfusion injury, oxidative damage, and apoptosis. Clinical evidence remains heterogeneous and is largely confined to short-term studies and surrogate outcomes (blood pressure, lipids, oxidative biomarkers, endothelial function), with scarce data on hard cardiovascular endpoints or event reduction. Priorities include standardized, chemotype-controlled formulations with PK/PD-guided dosing and adequately powered randomized trials that assess safety and herb-drug interactions.