Ginsenoside Rc exerts protective effects against cerebral ischemia‒reperfusion injury by boosting the Nrf2 pathway through targeted activation of Sirt1.

Ginsenoside Rc (G-Rc), a major active ingredient of Panax ginseng, has protective effects against various pathological alterations associated with diseases. Nonetheless, the potential benefits of G-Rc in treating cerebral ischemia-reperfusion (CIR) injury remain inadequately explored. In the present study, we evaluated the potential effects of G-Rc on CIR injury via cellular and animal models and explored the underlying mechanisms. Oxygen-glucose deprivation and reoxygenation (OGD/R)-induced neurons treated with G-Rc exhibited a marked reduction in apoptosis, oxidative stress, and inflammation. Rats treated with G-Rc presented significant reductions in neurological deficits, cerebral infarction, and pathological alterations resulting from CIR injury. Moreover, neuronal death, oxidative stress damage, and the inflammatory response in the brains of rats with CIR injury were markedly ameliorated by G-Rc treatment. Molecular docking, molecular dynamics simulations, and relevant experiments validated Sirtuin 1 (Sirt1) as a target of G-Rc. G-Rc increased Sirt1 expression and augmented its enzymatic activity. Notably, G-Rc promoted the activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) by targeting Sirt1. G-Rc failed to induce Nrf2 activation in Sirt1-silenced neurons. Furthermore, the benefits of G-Rc in defending against OGD/R damage were strongly negated by pharmacologically suppressing Nrf2. These observations indicate that G-Rc offers considerable benefits in treating CIR injury in experimental models. These beneficial effects are achieved by enhancing Nrf2 activation via the targeting of Sirt1. This study emphasizes the potential utilization of G-Rc as a pharmaceutical candidate for treating CIR damage.