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Ginsenoside Rb1 targets the NRF2-PPARγ-ACSL4 axis to inhibit PTECs ferroptosis
Binghong Tan1, Zhifen Wu1, Suwei Wang1
1Department of Nephrology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
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..
Insights
Ginsenoside Rb1 (Rb1) effectively treats acute kidney injury (AKI) by inhibiting ferroptosis, outperforming Ferrostatin-1. Rb1 activates the NRF2-PPARγ-ACSL4 pathway, offering a promising therapeutic strategy for AKI.
Area of Science:
- Nephrology
- Pharmacology
- Cell Biology
Background:
- Ferroptosis, a cell death pathway linked to lipid peroxidation, is a key factor in acute kidney injury (AKI).
- Current ferroptosis inhibitors like Ferrostatin-1 (Fer-1) have limitations.
- Ginsenoside Rb1 (Rb1), from Panax ginseng, shows potential for inhibiting ferroptosis.
Purpose of the Study:
- To investigate the therapeutic effects and mechanisms of Rb1 in treating AKI.
- To compare Rb1's efficacy against Fer-1 in preventing ferroptosis in kidney cells.
Main Methods:
- Evaluated renal function, tissue damage, and ferroptosis markers in mice and HK-2 cells.
- Utilized network pharmacology and molecular docking to identify Rb1 targets.
- Employed transcriptome sequencing and in vivo/in vitro validation to elucidate mechanisms.
Main Results:
- Rb1 significantly improved renal function and reduced kidney damage and inflammation in AKI models.
- Rb1 demonstrated superior ferroptosis inhibition compared to Fer-1 in proximal tubular epithelial cells.
- Identified Nuclear factor erythroid 2-related factor 2 (NRF2) as a direct target, with Rb1 activating the NRF2-PPARγ-ACSL4 axis to inhibit lipid peroxidation.
Conclusions:
- Rb1 effectively mitigates AKI by inhibiting ferroptosis through the NRF2-PPARγ-ACSL4 pathway.
- Rb1's established safety profile and superior efficacy suggest it as a potential therapeutic agent for AKI.
- Provides scientific evidence for Rb1's role in anti-ferroptosis therapy for kidney diseases.
