Cytochrome P450-derived Polyunsaturated Fatty Acid Metabolites as Modulators of Tumoral Hypoxia-induced Angiogenesis: From Mechanism to Anticancer Therapeutic Perspectives

Polyunsaturated Fatty Acids (PUFAs) are essential components of the human diet and physiology. Their biotransformation generates bioactive metabolites with regulatory functions in inflammation, vascular homeostasis, and tumor progression. Among these, arachidonic acid derivatives mediated by cytochrome P450 (CYP) enzymes, such as Epoxyeicosatrienoic acids (EETs) and Hydroxyeicosatetraenoic acids (HETEs), have emerged as key modulators of angiogenesis in the hypoxic tumor microenvironment. This review addresses the metabolic mechanisms that regulate the conversion of PUFAs by the CYP2C, CYP2J, and CYP4A/F families, emphasizing their role in activating signaling pathways such as VEGF/VEGFR and HIF-1, which impact cell proliferation, migration, and survival. Likewise, the therapeutic implications of modulating these PUFAs-metabolizing enzymes are analyzed, including the potential of EETs and 20-HETE analogs as pharmacological targets, with a view to developing new strategies for hypoxia-induced angiogenesis in cancer cells.