Ginsenoside Rg1 attenuates PM_2.5-induced neurotoxicity by suppressing ferroptosis via the Nrf2/GPx4 axis

Panax ginseng C.A. Mey. (Araliaceae) is prescribed in traditional Chinese medicine for cognition-related complaints (e.g., "Yi-Zhi") and to treat deficits such as forgetfulness. Given growing concerns about fine particulate matter (PM_2.5)-associated neurobehavioral impairment, we examined whether ginsenoside Rg1, a major ginseng saponin, can protect against PM_2.5-evoked neurotoxicity and thus provide experimental support for this cognition-related traditional use of ginseng.

To investigate whether ferroptosis contributes to PM_2.5-induced neurotoxicity and to determine whether ginsenoside Rg1 counteracts this injury through Nrf2-dependent restoration of the GPx4 antioxidant defense.

C57BL/6 mice and HT22 hippocampal neuronal cells were exposed to PM_2.5 and treated with or without Rg1. Behavioral performance, mitochondrial ultrastructure, and ferroptosis-related indices (Fe²⁺ accumulation and lipid peroxidation) were assessed together with the Nrf2/GPx4 antioxidant axis. Ferrostatin-1 was used as a reference ferroptosis inhibitor. ML385 and Nrf2 siRNA were used to evaluate the role of Nrf2 in Rg1-mediated protection.

PM_2.5 exposure led to cognitive impairment, mitochondrial condensation/shrinkage, and iron-dependent lipid peroxidation, accompanied by alterations in Nrf2 and suppression of GPx4. Rg1 markedly attenuated these alterations and showed efficacy comparable to ferrostatin-1. Pharmacological inhibition or knockdown of Nrf2 largely abolished the protective effects of Rg1.

PM_2.5 induces ferroptosis-associated neurotoxicity, and Rg1 confers protection at least in part via Nrf2-dependent restoration of GPx4-centered antioxidant defense.