Capsiate attenuates atherosclerosis by activating Nrf2/GPX4 pathway and reshaping the intestinal microbiota in ApoE

Atherosclerosis (AS) is the basis of cardiovascular diseases (CVDs) and remains the major contributor to death worldwide. Capsiate is derived from sweet pepper fruit and exhibits numerous pharmacological activities. The objective of this study was to elucidate the protective role of capsiate in atherosclerosis by examining its effect and the underlying regulatory pathways. Here, we showed that capsiate treatment alleviates atherosclerosis in atherosclerosis-prone apolipoprotein E-deficient (ApoE IMPORTANCE: Capsiate has been found to inhibit fat accumulation, promote energy metabolism, and exhibit anti-inflammatory and antioxidative properties. However, there has still been no study on the ferroptosis and gut microbiota of capsiate in atherosclerosis (AS) mouse models. Our study is the first to report on the reshaping of the structure of the gut microbiota by capsiate in AS, and to explore the potential mechanism underlying the improvement of AS. In this study, we demonstrated that capsiate could effectively alleviate high-fat diet-induced AS in apolipoprotein E-deficient mice by inhibiting inflammatory response, improving serum lipid profiles, activating transient receptor potential vanilloid subfamily member 1 pathway, and suppressing ferroptosis. Moreover, the study reported the potential of gut microbiota as mediators of capsiate therapy for AS in animal models. Therefore, these findings may provide robust experimental support for the clinical use of capsiate for AS treatment.