Panax notoginseng
saponins (PNS), the primary medicinal ingredient of Panax notoginseng, mitigates
cerebral ischemia-
reperfusion injury (CIRI) by inhibiting
inflammation, regulating oxidative stress, promoting angiogenesis, and improving microcirculation. Moreover, PNS activates nuclear factor erythroid 2-related factor 2 (Nrf2), which is known to inhibit ferroptosis and reduce
inflammation in the rat brain. However, the molecular regulatory roles of PNS in CIRI-induced ferroptosis remain unclear. In this study, we aimed to investigate the effects of PNS on ferroptosis and
inflammation in CIRI. We induced ferroptosis in SH-SY5Y cells via
erastin stimulation and
oxygen glucose deprivation/re-oxygenation (OGD/R) in vitro. Furthermore, we determined the effect of PNS treatment in a rat model of
middle cerebral artery occlusion/reperfusion and assessed the underlying mechanism. We also analyzed the changes in the expression of ferroptosis-related
proteins and inflammatory factors in the established rat model. OGD/R led to an increase in the levels of ferroptosis markers in SH-SY5Y cells, which were reduced by PNS treatment. In the rat model, combined treatment with an Nrf2 agonist, Nrf2 inhibitor, and PNS-Nrf2 inhibitor confirmed that PNS promotes Nrf2 nuclear localization and reduces ferroptosis and inflammatory responses, thereby mitigating
brain injury. Mechanistically, PNS treatment facilitated Nrf2 activation, thereby regulating the expression of
iron overload and lipid peroxidation-related
proteins and the activities of
anti-oxidant enzymes. This cascade inhibited ferroptosis and mitigated CIRI. Altogether, these results suggest that the ferroptosis-mediated activation of Nrf2 by PNS reduces
inflammation and is a promising therapeutic approach for CIRI.