Ginsenoside Rd alleviates atherosclerosis by inhibiting adipocyte ferroptosis in perivascular adipose tissues

Background Ginsenoside Rd (Rd) is an active ingredient in Panax ginseng Meyer and can be absorbed into the adipose tissue. Here, we aimed to investigate the impact of Rd on atherosclerosis (AS) and explore the mechanism. Methods We constructed an AS model by feeding ApoE -/- mice with a standard Western high-fat diet, treated with Rd, and combined RORC and TIGAR adipocyte-specific adeno-associated virus infection. An inflammatory adipocyte model (3T3-L1) was induced by LPS, and a lipid accumulation model in adipocytes was induced by palmitic acid. We investigated the role of the Rd-mediated RORC/TIGAR axis in adipocyte inflammation, oxidative stress, and ferroptosis through lentiviral vectors and the ferroptosis activator erastin. The interactions between RORC and TIGAR were examined. Next, the degree of lipid peroxidation and ferroptosis within perivascular adipose tissues (PVAT) in mice and 3T3-L1 cells was assessed. Results Rd improved PVAT dysfunction and alleviated endothelial inflammation in AS mice. Ginsenoside Rd targeted and inhibited RORC expression in adipocytes within the PVAT of mice. The transcription factor RORC occupied the TIGAR promoter to repress TIGAR transcription. Reactivation of RORC reversed the therapeutic benefit of Rd on AS, and reactivation of TIGAR also alleviated AS exacerbated by RORC. Rd reached therapeutic benefits by inhibiting RORC expression in adipocytes within PVAT, weakening its inhibitory effect on TIGAR, and further inhibiting adipocyte ferroptosis. Conclusion Rd targets RORC to activate TIGAR expression and block adipocyte ferroptosis in PVAT, thereby inhibiting AS.