Synergistic regulation of tumor angiogenesis via flavonoid modulation of lncRNAs: Mechanistic insights and therapeutic potential

Angiogenesis is a hallmark process of tumor growth, metastatic progression, and therapeutic resistance. The role of long noncoding RNAs (lncRNAs) in the regulation of angiogenesis has emerged as a critical factor influencing cancer progression. Flavonoids are natural polyphenolic compounds known for antioxidant and anti-inflammatory activities and have been recognized for their potential to regulate epigenetic and transcriptional networks involved in angiogenesis. This review seems to incorporate recent experimental evidence supporting that flavonoids such as quercetin, luteolin, curcumin, and resveratrol modulate angiogenesis-related lncRNAs (MALAT1, HOTAIR, PVT1, MEG3), leading to the inhibition of VEGF/HIF-1α, PI3K/Akt/mTOR, and NF-κB signaling pathways, which reduces endothelial proliferation and neovascularization. The recent advances in flavonoid bioavailability through nanoformulation, like liposomes, PLGA nanoparticles, and phytosomes, result in increased tumor specificity and more precise delivery. The quantitative evidence from numerous in vitro and in vivo studies has consistently demonstrated that flavonoid lncRNA modulation leads to a significant reduction in micro vessel density, expression of VEGF, and tumor burden. Improved bioavailability with more advanced nanoformulation and enhancement in preclinical validation of flavonoid lncRNA therapeutics, despite the remaining challenges like limited clinical data and off-target effects, offer low-toxicity targeted means of reprogramming tumor angiogenesis and overcoming resistance to the current therapies.