Cannabidiol attenuates atherosclerosis in male ApoE-/- mice with sex-dependent lipidomic and proteomic remodeling.

Cannabidiol (CBD), a non-psychoactive phytocannabinoid from Cannabis sativa, exhibits anti-inflammatory and antioxidant properties. We therefore hypothesized that CBD may modulate atherosclerosis development; however, preclinical evidence remains limited and sex-specific effects are poorly understood. Male and female apolipoprotein E-deficient (ApoE-/-) mice were fed a Western-type diet for 12 weeks and received either a CBD nanoemulsion (≈80 mg/kg/day) or vehicle via drinking water. Atherosclerosis was quantified by aortic plaque area, and lipidomic profiling together with aortic root proteomics were used to characterize CBD-induced metabolic changes. CBD treatment significantly reduced aortic plaque area in male but not female mice, without affecting body weight or standard serum lipid parameters. Untargeted lipidomics revealed sex-specific remodeling of the serum lipidome in males, including enrichment of ether-linked triacylglycerols, a class connected to ether-lipid metabolism; however, no lipid class emerged as a robust correlate of plaque burden. Proteomic analysis identified male-specific downregulation of mitochondrial oxidative and stress-related pathways, consistent with reduced vascular oxidative burden. In vitro, CBD attenuated oxLDL-induced oxidative stress and inflammatory activation in endothelial cells, supporting a direct vascular effect. CBD elicited no comparable molecular or plaque changes in females. Collectively, chronic CBD administration exerts a sex-dependent, anti-atherogenic effect in male ApoE-/- mice, associated with downregulation of mitochondrial oxidative metabolism and attenuation of endothelial oxidative and inflammatory activation, alongside remodeling of ether-linked lipid metabolism whose contribution to plaque protection remains to be established. These findings highlight the importance of incorporating sex-specific responses in future mechanistic and translational studies of CBD in atherosclerosis.