Statin-Mediated Modulation of Nrf2 Signaling: Mechanisms and Therapeutic Implications in Atherosclerosis

Statins are the cornerstone of lipid-lowering therapy and exert significant pleiotropic effects, including antioxidant and anti-inflammatory actions, which contribute to statin-mediated cardiovascular benefits. A key mechanism underlying these effects is the indirect activation of the nuclear factor erythroid 2-related factor 2 (Nrf2) transcription factor. This review critically assesses the molecular pathways through which statins modulate Nrf2 signaling, primarily through the PI3K/Akt and ERK pathways, which results in the nuclear translocation of Nrf2 and the transactivation of a battery of cytoprotective genes (e.g., heme oxygenase-1 (HO-1), Nicotinamide Adenine Dinucleotide (Phosphate) (reduced) (NAD(P)H) quinone oxidoreductase-1 (NQO1), catalytic subunit of glutamate-cysteine (GCLC)). This review synthesized evidence on the mechanism through which Nrf2 modulation stabilizes atherosclerotic plaques by mitigating oxidative stress and inflammation within the vascular wall. Furthermore, we explore the cell-type-specific effects of these findings within the complex plaque microenvironment and discuss any unresolved questions, including the therapeutic potential and pharmacokinetic challenges of combining statins with direct Nrf2 activators. Thus, by extending beyond a descriptive summary, this review provides a mechanistic integration of the statin-Nrf2 axis and identifies key frontiers for future research, emphasizing the need to harness these pleiotropic effects for improved cardiovascular outcomes.