Ginsenoside Rb1 Targets the HRD1-STING Axis to Mitigate Cholesterol-Induced VSMC Senescence

BACKGROUND: Vascular smooth muscle cells (VSMCs) are crucial components of the arterial wall, playing a vital role in maintaining vascular integrity and function. Previous studies have identified HRD1 as a potential target for alleviating senescence in VSMCs. Ginsenoside Rb1 has been shown to counteract endothelial cell senescence triggered by H₂O₂ or oxidized LDL. METHODS: In this study, Rb1 was investigated to determine if it could protect VSMCs from cholesterol-induced senescence. VSMCs were pretreated with Rb1 and subsequently exposed to cholesterol to evaluate its effects on SA-β-gal activity, reactive oxygen species (ROS) generation, cell viability, and STING pathway activation. RESULTS: Rb1 treatment significantly reduced the proportion of SA-β-gal-positive cells induced by cholesterol. Moreover, Rb1 suppressed the activation of endoplasmic reticulum (ER) stress markers and inhibited STING signaling. HRD1 knockdown abrogated the Rb1-mediated reduction of ROS production. Similarly, both Rb1 and an STING inhibitor decreased cholesterol-induced mitochondrial ROS (MitoSOX) levels. CONCLUSION: These findings indicate that Rb1 protects VSMCs against cholesterol-induced senescence by preserving HRD1 expression, mitigating ER stress, and maintaining mitochondrial function. Therefore, Rb1 holds therapeutic potential for preventing vascular diseases associated with VSMC senescence by modulating the HRD1 and STING pathways.