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Review
. 2023 May 11;19(9):2678-2694.
doi: 10.7150/ijbs.81892. eCollection 2023.

Emerging Role of Ferroptosis in Diabetic Kidney Disease: Molecular Mechanisms and Therapeutic Opportunities

Hui Wang  1   2   3   4 , Dongwei Liu  1   2   3   4 , Bin Zheng  1   2   3   4 , Yang Yang  5 , Yingjin Qiao  6 , Shiyang Li  1   2   3   4 , Shaokang Pan  1   2   3   4 , Yong Liu  1   2   3   4 , Qi Feng  1   2   3   4 , Zhangsuo Liu  1   2   3   4
Affiliations
Review

Emerging Role of Ferroptosis in Diabetic Kidney Disease: Molecular Mechanisms and Therapeutic Opportunities

Hui Wang et al. Int J Biol Sci. .

Abstract

Diabetic kidney disease (DKD) is one of the most common and severe microvascular complications of diabetes mellitus (DM), and has become the leading cause of end-stage renal disease (ESRD) worldwide. Although the exact pathogenic mechanism of DKD is still unclear, programmed cell death has been demonstrated to participate in the occurrence and development of diabetic kidney injury, including ferroptosis. Ferroptosis, an iron-dependent form of cell death driven by lipid peroxidation, has been identified to play a vital role in the development and therapeutic responses of a variety of kidney diseases, such as acute kidney injury (AKI), renal cell carcinoma and DKD. In the past two years, ferroptosis has been well investigated in DKD patients and animal models, but the specific mechanisms and therapeutic effects have not been fully revealed. Herein, we reviewed the regulatory mechanisms of ferroptosis, summarized the recent findings associated with the involvement of ferroptosis in DKD, and discussed the potential of ferroptosis as a promising target for DKD treatment, thereby providing a valuable reference for basic study and clinical therapy of DKD.

Keywords: diabetic kidney disease (DKD); ferroptosis; molecular mechanisms; regulators; treatment progress.

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Conflict of interest statement

Competing Interests: The authors have declared that no competing interest exists.

Figures

Figure 1
Figure 1
Mechanisms and major regulators of ferroptosis. Iron metabolism disorder, lipid peroxidation and decreased antioxidant capacity are involved in the occurrence of ferroptosis, and several key regulators (e.g., system Xc-, GPX4, p53 and ACSL4) play an important role in monitoring ferroptosis. Some recently developed compounds can induce or inhibit ferroptosis by targeting these key regulators.
Figure 2
Figure 2
The crosstalk between ferroptosis and other cellular processes of DKD. The overproduction of ROS leads to different kinds of downstream impairments, including ferroptosis. Meanwhile, the Fenton reaction containing excess free iron is one of the main pathways to produce ROS. Ferroptosis and inflammation can affect each other and tend to form an autoamplification loop. In mitochondria, the opening of VDACs plays a key role in mitochondrial dysfunction during ferroptosis, and multiple metabolic enzymes are influenced by ferroptosis.
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