Palmitoylethanolamide as an Intestinal Gatekeeper: Linking Inflammation, Angiogenesis and Colorectal Cancer Interception

Angiogenesis is a major determinant of tumor growth, progression and metastatic potential, and its persistent activation is closely intertwined with chronic inflammation. This relationship is particularly relevant in malignancies that arise through a prolonged inflammation-to-carcinogenesis continuum, where pathological vascular remodeling can sustain tissue hypoxia, immune-cell recruitment and the establishment of a tumor-permissive microenvironment. Colorectal cancer (CRC), especially in inflammation-associated settings, represents a paradigmatic example in which the inflammatory–angiogenic axis contributes to disease progression and unfavorable prognosis. Accordingly, identifying well-tolerated strategies capable of restraining pathological angiogenic pressure before overt neoplasia is established may have important preventive and therapeutic implications. This perspective focuses on palmitoylethanolamide (PEA), an endogenous N-acylethanolamine and prototypical autacoid local injury antagonist amide (ALIAmide) generated on demand as part of tissue homeostasis. PEA may act within a proposed multilevel intestinal homeostatic framework by preserving epithelial barrier integrity, limiting inflammatory amplification, modulating PPARα-dependent signaling and mast-cell reactivity, and restraining pro-angiogenic pathways, with context- and compartment-dependent effects on Akt/mTOR–HIF-1α/VEGF signaling. Importantly, direct preclinical evidence now supports PEA-related chemoprevention at two complementary levels: ultramicronized PEA reduced colon cancer cell proliferation and migration and decreased preneoplastic lesions and tumors in the murine azoxymethane model, whereas NAPE-PLD-engineered Lactobacillus paracasei F19 (pNAPE-LP) increased local PEA and reduced tumor burden, epithelial proliferation and angiogenesis in AOM/DSS colitis-associated CRC while modulating Akt/mTOR/p70S6K–HIF-1α signaling. These findings move the PEA–CRC relationship beyond a purely hypothetical association while remaining preclinical. We therefore propose that reinforcement of PEA signaling, through supplementation, PEA-oriented pharmacological strategies or engineered local biosynthesis, deserves investigation as a cancer-interception approach aimed at maintaining angiogenic and inflammatory homeostasis before autonomous tumor biology becomes established. This concept should not be interpreted as established clinical CRC prevention or as a substitute for conventional anticancer therapy.