PI3K/AKT signaling pathway: new strategies for treating atherosclerosis with plant-derived compounds

Atherosclerosis (AS) is a chronic vascular inflammatory disease driven by lipid deposition, whose clinical management remains constrained by the limitations of existing pharmacological interventions. This review systematically elucidates the molecular mechanisms by which plant-derived compounds modulate AS through targeted regulation of the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Studies indicate that plant-derived compounds-such as terpenoids (e.g., artemisinin and tanshinone IIA) and alkaloids (e.g., berberine)-effectively attenuate the progression of AS via bidirectional modulation of the PI3K/AKT pathway. In early stages, suppression of this pathway downregulates downstream mechanistic target of rapamycin (mTOR) and nuclear factor-kappa B (NF-κB) protein expression, thereby mitigating inflammatory responses and lipid accumulation to inhibit plaque formation. Conversely, during advanced disease phases, moderate activation of the pathway upregulates key effectors, including autophagy-related protein (Beclin-1), glutathione (GSH), and glutathione peroxidase 4 (GPX4), promoting ferroptosis and autophagy in abnormal cells and thereby enhancing the stability of established plaques. It is noteworthy that the low bioavailability of plant-derived compounds and the stage-specific nature of pathway modulation remain critical challenges for clinical translation. In this review, we deepen the mechanistic understanding of plant-based interventions against AS and provide a theoretical foundation and innovative perspectives for the development of future botanically derived AS therapeutics.