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Updated: Sep 22, 2025
Author Spotlight: Tracing the Ferroptotic Signatures and Cell Death Dynamics in Medulloblastoma for Advanced Therapeutics
Published on: March 15, 2024
Induction of ferroptosis selectively eliminates senescent tubular cells
Chieh M Liao1, Vera C Wulfmeyer1, Rongjun Chen2
1Department of Nephrology and Hypertension, Medical School Hannover, Hannover, Germany.
Abstract:
The accumulation of senescent cells is an important contributor to kidney aging, chronic renal disease, and poor outcome after kidney transplantation. Approaches to eliminate senescent cells with senolytic compounds have been proposed as novel strategies to improve marginal organs. While most existing senolytics induce senescent cell clearance by apoptosis, we observed that ferroptosis, an iron-catalyzed subtype of regulated necrosis, might serve as an alternative way to ablate senescent cells. We found that murine kidney tubular epithelial cells became sensitized to ferroptosis when turning senescent. This was linked to increased expression of pro-ferroptotic lipoxygenase-5 and reduced expression of anti-ferroptotic glutathione peroxidase 4 (GPX4). In tissue slice cultures from aged kidneys low dose application of the ferroptosis-inducer RSL3 selectively eliminated senescent cells while leaving healthy tubular cells unaffected. Similar results were seen in a transplantation model, in which RSL3 reduced the senescent cell burden of aged donor kidneys and caused a reduction of damage and inflammatory cell infiltration during the early post-transplantation period. In summary, these data reveal an increased susceptibility of senescent tubular cells to ferroptosis with the potential to be exploited for selective reduction of renal senescence in aged kidney transplants.
Insights
Senescent cells accelerate kidney aging and transplant rejection. Researchers found that inducing ferroptosis, a form of cell death, selectively eliminates these harmful cells, offering a new therapeutic strategy for kidney health.
Area of Science:
- Gerontology
- Nephrology
- Cellular Biology
Background:
- Cellular senescence contributes to kidney aging, chronic kidney disease, and transplant outcomes.
- Current senolytic therapies primarily induce apoptosis to clear senescent cells.
- Ferroptosis, an iron-dependent cell death, is explored as an alternative senolytic mechanism.
Purpose of the Study:
- To investigate ferroptosis as a selective method for eliminating senescent kidney cells.
- To determine if senescent kidney cells exhibit increased susceptibility to ferroptosis.
- To evaluate the therapeutic potential of ferroptosis induction in aged kidney transplantation.
Main Methods:
- Murine kidney tubular epithelial cells were induced into senescence.
- Gene expression of lipoxygenase-5 and glutathione peroxidase 4 (GPX4) was analyzed.
- Aged kidney tissue slices and a kidney transplantation model were treated with the ferroptosis inducer RSL3.
Main Results:
- Senescent kidney tubular cells showed increased sensitivity to ferroptosis.
- This sensitization was associated with upregulated lipoxygenase-5 and downregulated GPX4.
- RSL3 selectively eliminated senescent cells in aged kidney tissue and reduced damage in a transplant model.
Conclusions:
- Senescent kidney tubular cells are uniquely susceptible to ferroptosis.
- Targeting ferroptosis offers a novel strategy to reduce renal senescence in aged kidney transplants.
- This approach may improve outcomes for marginal donor kidneys and reduce transplant complications.
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