Targeting NF-κB Signaling with Natural Products: A Promising Therapeutic Strategy for Cardiovascular Diseases

Cardiovascular diseases (CVDs) remain the primary cause of human morbidity and mortality in the world. Inflammation, oxidative stress, and vascular remodeling are the key factors that make CVDs worse. The nuclear factor κB (NF-κB) signaling pathway is a major regulator in the progression of CVDs. NF-κB activates wrongly, induces the secretion of pro-inflammatory cytokines (including TNF-α, IL-6, and IL-1β), and enhances reactive oxygen species (ROS) generation. These accelerate endothelial dysfunction, myocardial damage, and atherosclerotic plaque development. Natural products are structurally diverse, multi-targeted, and low toxicity. They offer a promising way to prevent and treat cardiovascular disease by modulating the NF-κB signaling pathway. This review summarizes the recent studies about using natural products (including flavonoids, terpenoids, alkaloids, polyphenols, and polysaccharides) to treat CVDs through the NF-κB pathway, with a critical analysis of evidence strength according to CVDs indication (atherosclerosis, myocardial ischemia/reperfusion injury, pulmonary arterial hypertension, etc.) and study type (in vitro, in vivo animal, and human clinical research). We detail their molecular mechanisms, such as inhibiting the nuclear translocation of NF-κB p65, downregulating IκB phosphorylation, blocking upstream signaling (e.g., TLR4/MyD88, PI3K/Akt, MAPK), and affecting with other pathways (e.g., Nrf2/HO-1, SIRT1) to reduce inflammation and oxidative stress together. We also detail the effects of these natural products in various CVDs models, including atherosclerosis, hypertension, myocardial ischemia/reperfusion injury, diabetic cardiomyopathy, and pulmonary arterial hypertension, highlighting the characteristics of their treatments. Finally, we discuss the challenges of bringing natural products into the clinic and share some ideas to solve difficulties, with an in-depth critical analysis of the translational bottlenecks (poor bioavailability, unclear structure-activity relationships, incomplete mechanistic elucidation, and lack of large-scale clinical trials) and their underlying causes across different natural product classes. In summary, this review offers new perspectives on developing natural product-based therapies targeting the NF-κB signaling pathway for CVDs. It offers useful references for both preclinical studies and clinical applications.