Anastellin: A Fibronectin-Derived Peptide Targeting the Tumor Microenvironment Through ECM Modulation

Anastellin is a fibronectin-derived peptide originating from the first fibronectin type III (FNIII1) domain that exhibits potent anti-angiogenic and anti-tumor activity through extracellular matrix (ECM) modulation. Unlike fully folded fibronectin domains, anastellin adopts a partially unfolded β-sandwich conformation that exposes hydrophobic β-strand regions, enabling β-strand exchange with neighboring fibronectin type III repeats. This unique biophysical property destabilizes native fibronectin folding and promotes the formation of highly ordered fibronectin polymers known as superfibronectin, fundamentally altering ECM architecture and mechanics. At the biochemical level, anastellin-induced ECM reorganization disrupts integrin clustering and focal adhesion maturation, leading to attenuation of focal adhesion kinase and Src signaling. These upstream events suppress key downstream pathways, including phosphoinositide 3-kinase/protein kinase B (PI3K/AKT)–mediated survival signaling and rat sarcoma virus–mitogen-activated protein kinase (RAS–MAPK)–dependent proliferation and angiogenesis. Anastellin additionally modulates stress-responsive signaling pathways, such as p38 mitogen-activated protein kinase and nuclear factor kappa-light-chain-enhancer of activated B cells, contributing to endothelial cell cycle arrest and inhibition of tumor vascularization. This review integrates current biochemical, biophysical, and translational insights into anastellin function, with particular emphasis on its conformational dynamics, redox sensitivity, and extracellular matrix–targeting mechanism of action. We further discuss emerging challenges related to pharmacokinetics, delivery strategies, and patient stratification, highlighting future directions for the development of anastellin-based ECM-directed therapies.