Wild Cordyceps Polysaccharides Alleviate Atherosclerosis by Attenuating Macrophage Cholesterol Accumulation Through the PPARγ-LXRα-ABCA1/ABCG1 Pathway

Cordyceps has been clinically used to treat atherosclerosis (AS) since the 1980s. However, the active components responsible for its effects and the underlying mechanisms remain poorly understood. In this study, we aimed to explore the anti-AS effects and mechanisms of action of wild Cordyceps polysaccharides (WCP). The molecular weight, monosaccharide composition, and structural characteristics of WCP were analyzed. Furthermore, the anti-AS effects of WCP were evaluated using apolipoprotein E knockout (<i>Apoe</i>^-/-) mice fed high-fat diets. The mechanisms underlying WCP's anti-atherosclerotic activity were elucidated in <i>Apoe</i>^-/- mice and oxidized low-density lipoprotein-loaded RAW264.7 macrophages. We found that WCP is composed of galactose, glucose, and mannose, with a molar ratio of 1:1.1:1.2. The average molecular weights of WCP are 1486 and 26 kDa. WCP significantly attenuated the progression of AS, as evidenced by reduced plaque formation in the aortic root valve area. Notably, WCP reduced cholesterol accumulation in macrophages by upregulating the expression of ATP-binding cassette transporter protein 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1), both <i>in vivo</i> and <i>in vitro</i>. Importantly, we identified peroxisome proliferator-activated receptor-gamma (PPARγ) as a critical target of WCP in macrophages, as confirmed by siRNA knockdown experiments. The ability of WCP to enhance the expression of cholesterol efflux-related genes in macrophages was markedly diminished upon suppression of PPARγ expression. In conclusion, our findings suggest that WCP mitigates the development of AS by activating the PPARγ-liver X receptor alpha (LXRα)-ABCA1/ABCG1 pathway, thereby reducing cholesterol accumulation in macrophages. This study provides new insights into how Cordyceps polysaccharide exerts anti-atherosclerotic effects and highlights its potential as a therapeutic agent for AS.