Targeting ferroptosis: a new therapeutic opportunity for kidney diseases

Abstract

Ferroptosis is a form of non-apoptotic regulated cell death (RCD) that depends on iron and is characterized by the accumulation of lipid peroxides to lethal levels. Ferroptosis involves multiple pathways including redox balance, iron regulation, mitochondrial function, and amino acid, lipid, and glycometabolism. Furthermore, various disease-related signaling pathways also play a role in regulating the process of iron oxidation. In recent years, with the emergence of the concept of ferroptosis and the in-depth study of its mechanisms, ferroptosis is closely associated with various biological conditions related to kidney diseases, including kidney organ development, aging, immunity, and cancer. This article reviews the development of the concept of ferroptosis, the mechanisms of ferroptosis (including GSH-GPX4, FSP1-CoQ1, DHODH-CoQ10, GCH1-BH4, and MBOAT1/2 pathways), and the latest research progress on its involvement in kidney diseases. It summarizes research on ferroptosis in kidney diseases within the frameworks of metabolism, reactive oxygen biology, and iron biology. The article introduces key regulatory factors and mechanisms of ferroptosis in kidney diseases, as well as important concepts and major open questions in ferroptosis and related natural compounds. It is hoped that in future research, further breakthroughs can be made in understanding the regulation mechanism of ferroptosis and utilizing ferroptosis to promote treatments for kidney diseases, such as acute kidney injury(AKI), chronic kidney disease (CKD), diabetic nephropathy(DN), and renal cell carcinoma. This paves the way for a new approach to research, prevent, and treat clinical kidney diseases.

Keywords: acute kidney disease; chronic kidney disease; ferroptosis; iron metabolism; natural compounds.

Figure 1

This figure shows the metabolic pathways involved in iron-dependent cell death. Iron-dependent lipid peroxidation drives iron death at the cellular level. Several aspects of iron metabolism, such as absorption, storage, and utilization, play important roles in regulating iron death. Additionally, activation of long-chain fatty acid CoA ligase 4 (LACS4), lysophosphatidyltransferase 5 (LPLAT5), lipid oxidase (LOX), or NADPH oxidase (NOX) in the lipid metabolism pathway promotes lipid peroxidation and iron death. The classic iron death suppression pathway involves the cysteine-glutamate reverse transporter (Xc-system), which induces the biosynthesis of GSH by facilitating cysteine (Cys) uptake. Using GSH as a cofactor, GPX4 reduces phospholipid hydroperoxides to their respective alcohols. The peroxidation of phospholipids can also be suppressed by the iron death inhibitor factor 1 (FSP1)-coenzyme Q10 (CoQ10) system. Furthermore, iron death is regulated by iron metabolism, including absorption, transport, storage, and utilization of iron. At the cellular level, non-heme iron enters cells through transferrin receptor 1 (TFR1)-mediated iron uptake by transferrin (TF) binding, or iron uptake independent of TF mediated by solute carrier family 39 member 14 (SLC39A14, also known as zinc transporter ZIP14). Additionally, iron engulfment mediated by heme degradation and nuclear receptor coactivator 4 (NCOA4) increases the labile iron pool (LIP), making cells more sensitive to iron death via the Fenton reaction. FPN, ferritin, Glu represents glutamate; GSSG, oxidized glutathione; HO1, heme oxygenase 1; KEAP1, kelch-like ECH-associated protein 1; NRF2, nuclear factor E2-related factor 2; PUFA, polyunsaturated fatty acid; PUFA-CoA, polyunsaturated fatty acid-coenzyme A; PUFA-PL, phospholipid containing polyunsaturated fatty acids (PUFA); and STEAP3, metalloreductase STEAP3.

Figure 2

The figure depicts the regulation of ferroptosis by multiple metabolic events (such as lipogenesis, autophagy, and mitochondrial TCA cycle) and signaling pathways (such as E-cadherin-NF2-Hippo-YAP pathway, glucose-regulated AMPK signaling, and p53 and BAP1 tumor suppressor function). See text for details. TfR, transferrin receptor; PL-OOH, phospholipid hydroperoxide; PUFA-PL, phospholipid with polyunsaturated fatty acid chain; ROS, reactive oxygen species; TCA, mitochondrial TCA cycle; Gln, glutamine; Glu, glutamate; αKG, α-ketoglutarate.

Figure 3

After intake of iron, Fe3+ is reduced by dcytb and then transported into enterocyte through DMT1. Dietary heme is absorbed by unknown mechanism and degraded in enterocyte by HO-1. Once exported by FPN, Fe3+ binds to transferrin (diferric transferrin, TF-Fe2), travels to tissues, and largely utilized in new red blood cells. Macrophage degraded senescent RBCs to recycle iron. Once needed, EPO, released by kidney, promotes erythropoiesis by HIF signaling pathway. The iron utilization of erythroid marrow and its recycling by macrophages represent the major iron circulation. Excess iron can be stored in hepatocytes through TFR1-mediated TF-Fe2 or SLC39A14-participated non-transferrin-bound iron (NTBI). The release of iron from enterocyte, red blood cells, and macrophages is precisely controlled by FPN, the body’s sole iron exporter, to maintain a relatively stable iron level. The peptide hepcidin, the master regulator of systemic iron homeostasis, is a circulating hormone synthesized by the liver. Recently, we identified RNF217 as a novel E3 ligase for mediating FPN degradation. Dcytb, duodenal cytochrome b; DMT1, divalent metal transporter 1; EPO, erythropoietin; FPN, ferroportin; TFR1, transferrin receptor 1; HO-1, heme oxygenase 1; HIF, hypoxia induced factor; RBCs, red blood cells; NTBI, non-transferrin-bound iron.

Figure 4

Under iron-deficient conditions (left), the majority of iron is bound to transferrin (TF), which binds to the transferrin receptor 1 (TFR1) at the cell surface followed by receptor-mediated endocytosis, resulting in ferric iron being released from TF and reduction to ferrous iron by an lysosomal reductase such as STEAP3. The ferrous iron is then transported into the lysosomal membrane by DMT1 and TRPML1/2, where it becomes part of the labile iron pool in the cytosol. Labile iron can be stored in the iron-storage protein ferritin or used to synthesize heme and iron-sulfur clusters in the mitochondria or in the cytosol. Iron can also be exported from the cell by the body’s sole iron exporter, ferroportin (FPN). In addition, the IRE/IRP system regulates the expression of iron-related proteins such as TFR1, ferritin and FPN, upregulating TFR1 and DMT1 expression and downregulating FPN and FTH/FTL expression. During iron overload (right), hepcidin expression is upregulated by either the canonical bone morphogenetic protein (BMP)/SMAD pathway or by IL-6-pSTAT3 inflammatory signaling, which in turn limits iron absorption by increasing FPN degradation. In response to excess iron, BMP6, together with HJV, activates type 1 (Alk2/3)and type 2 (BMPR2, ACVR2A) BMP serine threonine kinase receptors to phosphorylate R-SMAD (receptor-activated SMAD), leading to activation of BMP/SMAD signaling pathway. High concentration of TF-Fe2 interact with TFR1, resulting in forming complex of TFR2/HJV/HFE to enhance the BMP/SMAD signaling in regulating hepcidin. TMPRSS6 inhibits BMP/SMAD signaling by cleaving HJV. The IRP system not only downregulates iron uptake-related genes such as TFR1 and DMT1 expression, it also upregulates FPN and FTH/FTL expression. IRP2 mediated by SKP1-CUL1 E3 ubiquitin ligase and NCOA4 are degraded, while IPR1 works as aconitase to convert citrate to isocitrate due to conformational change. RNF217 is a recently identified E3 ligase that regulates the degradation of FPN. ACVR2A, activin receptor type-2A; ALK, activin receptor-like kinase; BMP6, bone morphogenetic protein 6; BMPR2, bone morphogenetic protein receptor type 2; DMT1, divalent metal transporter 1; EPO, erythropoietin; ERFE, erythroferrone; ETC, electron transport chain; FBXL5, F-box/LRR-repeat protein 5; FPN, ferroportin; FTH, ferritin heavy chain; FTL, ferritin light chain; JAK, Janus kinase; LIP, labile iron pool; NCOA4, nuclear receptor coactivator 4; NTBI, non-transferrin-bound iron; HJV, hemojuvelin; IL-6, interleukin 6; IRE, iron-responsive elements; IRP, iron-regulatory proteins; SLC39A14, solute carrier family 39 member 14; SMAD4, SMAD family member 4; SMAD7, SMAD family member 7; STAT3, signal transducer and activator of transcription 3; STEAP3, six-transmembrane epithelial antigen of prostate 3; TCA cycle, tricarboxylic acid cycle; TFR1, transferrin receptor 1; TFR2, transferrin receptor 2; TMPRSS6, transmembrane protease serine 6; TRPML1/2, Mucolipin TRP channel 1/2;UTRs, untranslated regions.

Figure 5

Mitochondria host a wide range of key metabolic processes (such as the tricarboxylic acid (TCA) cycle) and are a major source of reactive oxygen species (ROS). Separate mitochondria-localized defense systems have evolved to prevent mitochondrial lipid peroxidation and ferroptosis. For example, either the mitochondrial version of phospholipid hydroperoxide glutathione peroxidase 4 (GPX4) or dihydroorotate dehydrogenase (quinone), mitochondrial (DHODH) can specifically detoxify mitochondrial lipid peroxides. Moreover, the mitochondria-specific form of ferritin (FTMT) protects mitochondria from iron overload-induced oxidative injury, and mitoNEET (also known as CISD1) suppresses ferroptosis by limiting mitochondrial iron uptake. CoQ10, coenzyme Q10; FPN, ferroportin; FSP1, ferroptosis suppressor protein 1; GSH, glutathione; GSSG, glutathione disulfide; HO1, haem oxygenase 1; LIP, labile iron pool; PL-PUFA-OOH, polyunsaturated fatty acid-containing phospholipid hydroperoxides; PLOO·, phospholipid peroxyl radical; RNF217, E3 ubiquitin protein ligase RNF217; SLC25A39, probable mitochondrial glutathione transporter SLC25A39; SLC39A14, solute carrier family 39 member 14; TF, transferrin; TFR1, transferrin receptor protein 1.

Figure 6

Ferroptosis-related diseases that can present throughout the human lifespan.