Journal Article

Ginsenoside Rb1 targets the NRF2-PPARγ-ACSL4 axis to inhibit PTECs ferroptosis

Wu, Zhifen, Zheng, Luquan, Wang, Suwei, Yang, Xujia, Li, Li, Tan, Wei, Li, Ke, Tan, Binghong, Li, Jing, Lin, Lirong, Yang, Jurong

2026

Overview

Background Ferroptosis, an iron-dependent form of regulated cell death driven by lipid peroxidation, has emerged as a critical pathological mechanism in acute kidney injury (AKI). While pharmacologic targeting of ferroptosis holds therapeutic potential, clinically applicable inhibitors remain elusive, with even the classical inhibitor ferrostatin-1 (Fer-1) demonstrating limitations. Ginsenoside Rb1 (Rb1), a major active component of Panax ginseng, has recently been shown to inhibit ferroptosis in non-renal tissues. This study aimed to investigate the role and mechanism of Rb1 in treating AKI. Methods The protective and anti-ferroptotic effects of Rb1 on AKI were evaluated by assessing renal function, tissue damage, inflammation, ferrous iron, glutathione, malondialdehyde, and ferroptosis markers in C57BL/6 mice, as well as cell viability and ferroptosis-related indicators in HK-2 cells. Network pharmacology and molecular docking were employed to identify Rb1's target proteins. Transcriptome sequencing predicted further mechanisms underlying its anti-ferroptotic effects, which were subsequently validated through in vivo and in vitro experiments. Results The experimental results demonstrated that Rb1 administration significantly ameliorated renal dysfunction, attenuated tubular necrosis and inflammatory responses, while markedly suppressing ferroptosis-related indicators. Strikingly, Rb1 exhibited superior efficacy to Fer-1 in preventing ferroptosis in proximal tubular epithelial cells (PTECs) in vitro. Nuclear factor erythroid 2-related factor 2 (NRF2) was verified as a direct target for Rb1's ferroptosis-inhibitory effect. Mechanistic studies revealed that Rb1 selectively inhibits lipid peroxidation—the biochemical hallmark of ferroptosis—by activating the NRF2-PPARγ-ACSL4 axis.  Conclusion Given its established safety profile in human use, Rb1 represents a potential therapeutic agent for preventing and treating AKI, providing scientific evidence for its application in anti-ferroptosis therapy.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: ACSL4 / Acupuncture / Antibodies / Biotechnology industry / Cell death / Cell viability / Complementary & Alternative Medicine / Epithelial cells / Ferroptosis / Gene expression / Ginsenoside Rb1 / Ginsenosides / Glutathione / Ischemia / Kidneys / Lipid peroxidation / Lipids / Medical research / Medicine / Medicine & Public Health / NRF2 / Peroxisome proliferator-activated receptors / PPARγ / Proteins / PTEC / Reactive oxygen species / Reagents / Renal function / Traditional Chinese Medicine / Transcriptomes