2. Academic Validation
  3. Ginsenoside Rb1 targets the NRF2-PPARγ-ACSL4 axis to inhibit PTECs ferroptosis

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

  • Chin Med. 2026 Jan 8;21(1):19. doi: 10.1186/s13020-025-01292-x.
Binghong Tan # 1,  Zhifen Wu # 1,  Suwei Wang 1,  Wei Tan 1,  Lirong Lin 1,  Xujia Yang 1,  Luquan Zheng 1,  Jing Li 2,  Ke Li 3,  Jurong Yang 4,  Li Li 5
Affiliations

Affiliations

  • 1 Department of Nephrology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China.
  • 2 Department of Cardiology, The 924, Hospital of Chinese People's Liberation Army Joint Service Support Force, Guilin, China.
  • 3 Core Research Laboratory, The Second Affiliated Hospital of Xi'an Jiao Tong University, Xi'an, China.
  • 4 Department of Nephrology, The Third Affiliated Hospital of Chongqing Medical University, Chongqing, 401120, China. [email protected].
  • 5 National Key Laboratory for Prevention and Treatment of Multi-Organ Injury, National Clinical Research Center of Kidney Disease, Guangdong Provincial Institute of Nephrology, and Division of Nephrology, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, China. [email protected].
  • # Contributed equally.
PMID: 41508002 DOI: 10.1186/s13020-025-01292-x
Abstract

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..

Keywords

ACSL4; Ferroptosis; Ginsenoside Rb1; NRF2; PPARγ; PTEC.

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