2. Academic Validation
  3. Ginsenoside Rg1 attenuates PM2.5-induced neurotoxicity by suppressing ferroptosis via the Nrf2/GPx4 axis

Ginsenoside Rg1 attenuates PM2.5-induced neurotoxicity by suppressing ferroptosis via the Nrf2/GPx4 axis

  • J Ethnopharmacol. 2026 May 23:363:121464. doi: 10.1016/j.jep.2026.121464.
Haoyu Lu 1,  Xuezhen Li 1,  Jinze Liu 1,  Weining Zhang 1,  Zhongmei He 2,  Yan Zhao 2,  Jianan Geng 2,  Jia Zhou 2,  Weijia Chen 3,  Rui Du 4
Affiliations

Affiliations

  • 1 College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China.
  • 2 College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China; Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Changchun, 130118, China; Key Laboratory of Animal Production and Product Quality and Security, Ministry of Education, Changchun, 130118, China.
  • 3 College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China; Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Changchun, 130118, China; Key Laboratory of Animal Production and Product Quality and Security, Ministry of Education, Changchun, 130118, China. Electronic address: [email protected].
  • 4 College of Chinese Medicinal Materials, Jilin Agricultural University, Changchun, 130118, China; Jilin Provincial Engineering Research Center for Efficient Breeding and Product Development of Sika Deer, Changchun, 130118, China; Key Laboratory of Animal Production and Product Quality and Security, Ministry of Education, Changchun, 130118, China. Electronic address: [email protected].
PMID: 41775233 DOI: 10.1016/j.jep.2026.121464
Abstract

Ethnopharmacological relevance: 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 (PM2.5)-associated neurobehavioral impairment, we examined whether ginsenoside Rg1, a major ginseng saponin, can protect against PM2.5-evoked neurotoxicity and thus provide experimental support for this cognition-related traditional use of ginseng.

Aim of the study: To investigate whether Ferroptosis contributes to PM2.5-induced neurotoxicity and to determine whether ginsenoside Rg1 counteracts this injury through Nrf2-dependent restoration of the GPx4 antioxidant defense.

Materials and methods: C57BL/6 mice and HT22 hippocampal neuronal cells were exposed to PM2.5 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.

Results: PM2.5 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.

Conclusion: PM2.5 induces ferroptosis-associated neurotoxicity, and Rg1 confers protection at least in part via Nrf2-dependent restoration of GPx4-centered antioxidant defense.

Keywords

Ferroptosis; Ginsenoside Rg1; Lipid peroxidation; Neurotoxicity; Nrf2; PM(2.5).

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