Cimicifuga racemosa extract Ze 450 shifts macrophage immunometabolism and attenuates pro-inflammatory signaling

Extracts from the rhizomes of Cimicifuga racemosa (CRE) are well-studied for treating climacteric symptoms and considered as a safe alternative to hormone replacement therapy (HRT). Chronic low-grade inflammation, or "inflammaging," resulting from the loss of oestrogen's regulatory effect on the immune system, is increasingly recognized as a significant factor in the health of postmenopausal women, contributing to a higher risk for cardiovascular disease, osteoporosis, metabolic syndrome, and cognitive decline. Recent studies have suggested that CRE may exert anti-inflammatory effects, though the underlying mechanisms remain unclear. In this study, we aimed to investigate the effects of Cimicifuga racemosa extract Ze 450 on lipopolysaccharide (LPS)-induced inflammation in macrophages, as macrophage inflammation is crucial in the pathogenesis of several metabolic diseases associated with menopause. Our results demonstrated that CRE Ze 450 reduced the production of NO, IL-1α/β, IL-6, and IL-10, as well as the expression of the pro-inflammatory proteins iNOS, HIF-1α, and mTOR in LPS-stimulated macrophages. Moreover, we observed that Ze 450 induced a shift in energy production from oxidative phosphorylation (OXPHOS) to glycolysis. Mechanistically this was mediated by the modulation of TCA cycle and electron transport chain activity at an early stage, which was further accompanied by the reduction of metabolic signaling molecules such as succinate and citrate. In conclusion, our study identifies a novel mode of action for the Cimicifuga racemosa extract Ze 450, demonstrating its ability to regulate mitochondrial function and macrophage metabolism, but also highlighting its potential to improve the climacteric symptoms by mitigating pro-inflammatory signaling.