Wei Peng, Qiong Zhang, Tingjuan Wang, Zhijie Wang, Menghui Zhao, Yue Li, X. -B. Chen, Youqi Zhang, Jie Yang, Li Huang, Xiang Liu, Feifeng Li
Introduction: Elevated low-density lipoprotein cholesterol (LDL-C) is a major contributor to hyperlipidemia and cardiovascular risk. This study examined the association of LDL-C with metabolic abnormalities in a health examination population and investigated whether gypenosides (GPs) protect against LDL-induced cardiomyocyte injury through the miR-223/NLRP3 axis. Methods: A cross-sectional analysis was conducted in 19,862 adults undergoing routine health examinations. In parallel, H9C2 cardiomyocytes were exposed to LDL with or without GPs. Cell viability, cell cycle distribution, wound healing, Matrigel-based tube formation, oxidative stress, inflammatory markers, and miR-223/NLRP3-related signaling molecules were assessed. A miR-223 inhibitor and the NLRP3 inhibitor MCC950 were used to further examine the mechanism. Results: Elevated LDL-C was more common in middle-aged and older men and was associated with higher blood glucose, white blood cell count, body mass index, systolic blood pressure, total cholesterol, and triglycerides, together with lower HDL-C. In H9C2 cells, LDL induced abnormal proliferative activation and cell-cycle disturbance, reduced wound healing and tube-like network formation, increased ROS, NO, and LDH release, activated the NLRP3/NF-κB/p38/IL-6 pathway, and suppressed miR-223 expression. GPs attenuated these changes, restored miR-223 expression, and reduced inflammatory signaling. Inhibition of miR-223 weakened the protective effects of GPs, whereas MCC950 suppressed LDL-induced inflammatory activation. Conclusion: . More importantly, Gypenosides markedly alleviated LDL-induced cellular injury by restoring miR-223 expression and suppressing NLRP3-mediated inflammatory signaling. The inhibitory effect of MCC950 further supports a central role for NLRP3 in this process. Together, these findings suggest that Gypenosides may have therapeutic potential for hyperlipidemia-related myocardial injury.