Amentoflavone and cancer: mechanistic insights and translational perspectives.

Amentoflavone (AF) is a naturally occurring biflavonoid isolated from multiple medicinal plants and widely studied for anti-inflammatory and antioxidant activities. In oncology, AF has emerged as a pleiotropic small molecule that modulates interconnected signaling axes rather than a single node. Preclinical studies indicate that AF attenuates PI3K/Akt/mTOR signaling and NF-κB-dependent survival programs, disrupts Wnt/β-catenin-linked epithelial-mesenchymal transition (EMT), and modulates MAPK cascades to promote apoptosis and cell-cycle arrest. AF also interferes with pro-angiogenic signaling and VEGF-driven neovascularization. Across diverse cancer models, these activities translate into reduced proliferation, enhanced apoptosis, suppression of invasion/EMT, and inhibition of tumor-associated angiogenesis. However, translation remains limited by poor aqueous solubility, low oral exposure, and incomplete exposure-response and safety characterization. Recent drug delivery approaches (polymeric micelles, mixed nanomicelles, DSPE-PEG micelles) and rational combination strategies provide practical routes to improve systemic exposure and revisit AF in combination regimens. This review integrates mechanistic and tumor-specific evidence with a clear distinction between direct target binding and downstream pathway readouts, quantitative in vitro/in vivo endpoints, an expanded reference list using verifiable sources, and priorities for pharmacokinetic optimization, toxicity evaluation, and biomarker-guided early-phase development.