Phosphoinositide 3-kinase (PI3K), Protein kinase B (AKT), and Endothelial nitric oxide synthase (eNOS) (PI3K/AKT/eNOS)

The PI3K/AKT/eNOS pathway is a critical intracellular signaling cascade primarily involved in the regulation of endothelial cell function, vascular tone, cellular survival, metabolism, and angiogenesis. Activation of PI3K catalyzes the generation of lipid second messengers, leading to recruitment and phosphorylation of AKT (protein kinase B). Active AKT phosphorylates eNOS at Ser1177, increasing its enzymatic activity and promoting the synthesis of nitric oxide (NO), a key mediator of vascular relaxation and anti-inflammatory effects. Dysregulation of this pathway has been implicated in a wide array of diseases, including cancer, atherosclerosis, acute lung injury, and neurodegenerative disorders. Pharmacological modulation of this axis—either activation (e.g., in cardiovascular protection) or inhibition (e.g., in cancer)—is a major therapeutic strategy, although off-target and systemic effects pose safety challenges[1][2][3][4][5][7].

Other names

PI3K-AKT-eNOS pathwayPI3K–AKT–eNOS axisPI3K/AKT pathway (sometimes used when referring to the biological context that leads to eNOS activation)Phosphoinositide 3-kinase/Protein kinase B/Endothelial nitric oxide synthase pathway

Inhibition of PI3K or AKT reduces eNOS phosphorylation and NO production[2][3][7]. Activation of PI3K results in downstream AKT activation, which phosphorylates and activates eNOS, increasing NO synthesis[1][2][3][7]. Drugs that stimulate pathway activity can be protective (e.g., in cardiovascular disease); inhibitors can be anti-cancer by reducing cell survival.