Natural Products as Anti-Angiogenic Agents: Molecular Targets, Signaling Pathways, and Mechanistic Insights

Angiogenesis, the process of forming new blood vessels from pre-existing vasculature, is a tightly regulated physiological process that is essential for embryonic development, wound healing, tissue regeneration, and the maintenance of normal tissue homeostasis. However, its pathological activation plays a pivotal role in tumor progression, chronic inflammation, and other angiogenesis-dependent diseases. Current antiangiogenic therapies, though clinically effective, are often limited by toxicity, resistance, and high costs. In this context, natural products have emerged as promising sources of bioactive molecules with potent antiangiogenic activity and minimal adverse effects. This review comprehensively discusses the molecular pathways underlying angiogenesis, including the regulatory roles of VEGF, FGF, HIF-1α, COX-2, NF-κB, and PI3K/Akt/mTOR cascades, and their modulation by natural compounds. Various phytoconstituents, including curcumin, resveratrol, quercetin, kaempferol, epigallocatechin gallate, withaferin A, betulinic acid, and marine- derived metabolites, exhibit anti-angiogenic activity by inhibiting endothelial cell proliferation, migration, and extracellular matrix degradation, while simultaneously downregulating key angiogenic signalling pathways. Structure-activity relationship (SAR) insights reveal that polyphenolic and terpenoid scaffolds play crucial roles in these mechanisms. The review also highlights experimental models used for anti-angiogenic evaluation and discusses clinical translation challenges related to bioavailability and formulation optimization. Overall, natural products represent a diverse and sustainable reservoir for developing next-generation antiangiogenic therapeutics, offering multi-targeted mechanisms and improved safety profiles suitable for cancer prevention and treatment.