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The cell death induced by PAFs has characteristics of ferroptosis (A) Cell viability of HT1080 treated with M-PAF C16 (75 μM) or PAF C18 (100 μM) and different inhibitors. (B-D) Cell viability of U-2 OS(B), HK2(C) and HUVEC(D) cells treated with PAF C16 (100 μM) or PAF C18 (100 μM) and different inhibitors. The concentration of inhibitors: Fer-1 (2 μM), DFO (50 μM), Nec-1 (20 μM), Nec-1S (20 μM), Z-VAD-FMK (50 μM). (E) Super-high resolution microscopy images of HT1080 cells treated with control or PAF C16 (75 μM). Scale bar, 2 μm. (F-H) Flow cytometry analysis of fluorescence of BODIPY-C11 when HT1080 cells subjected to PAF C16, PAF C18 or M-PAF C16 with or without pretreatment of ferroptosis inhibitors. (I, J) Quantification of the mean fluorescence intensity of Liperfluo (I) and MitoPeDPP (J) in HT1080 cells treated with control, PAF C16 (75 μM) or RSL3 (0.2 μM). (K, L) Flow cytometry analysis of Mito-FerroGreen staining in HT1080 cells treated with PAF C16 (75 μM) for indicated time. (M) ATP levels in HT1080 cells treated with PAF C16 (75 μM). (N-P) Flow cytometry analysis of TMRE in HT1080 cells treated with PAF C16, M-PAF C16 or 2-O-methyl PAF C-16. (Q) The relative mRNA levels were measured by qRT-PCR in HT1080 cells treated with PAF C16 (75 μM). Data show mean ± s.d. of three independent experiments. For A-D, I-J, L-M, data show mean ± s.d. of three independent experiments. Unpaired two-sided Student’s t-test. Source data
Source publication
Synchronized ferroptosis contributes to nephron loss in acute kidney injury (AKI). However, the propagation signals and the underlying mechanisms of the synchronized ferroptosis for renal tubular injury remain unresolved. Here we report that platelet-activating factor (PAF) and PAF-like phospholipids (PAF-LPLs) mediated synchronized ferroptosis and...
Citations
... Like other types of programmed cell death, such as apoptosis, programmed necrosis and pyroptosis, ferroptosis has specific regulatory genes and death characteristics [11][12][13][14][15] . Ferroptosis has been shown to propagate through cell populations, resulting in spatiotemporal patterns of cell death with a wave-like appearance not previously observed in other forms of cell death [16][17][18][19][20][21] . However, the mechanism of ferroptosis propagation is currently unclear. ...
... However, the mechanism of ferroptosis propagation is currently unclear. Ferroptosis propagation has been observed not only in cells in vitro but also in ferroptosis-induced models in vivo and in ferroptosis-related physiological and disease processes such as embryogenesis, acute injury or neurodegenerative diseases, manifesting as large and continuous cell death and tissue damage [16][17][18][19][22][23][24] . This suggests that inhibiting the propagation of ferroptosis may alleviate or cure the above diseases. ...
... However, the molecular mechanisms driving ferroptosis propagation are unclear. Ferroptosis can also propagate in in vivo pathological conditions, such as acute injury and neurodegenerative diseases [16][17][18][19] . Therefore, exploring the molecular mechanism of ferroptosis propa gation is not only important for understanding the process of ferroptosis but also highly important for interventions targeting ferroptosis to treat diseases. ...
The mechanism of ferroptosis propagation is still unclear. Here our results indicate that the cells undergoing ferroptosis secrete Galectin-13, which binds to CD44 and inhibits the plasma membrane localization of SLC7A11 in neighboring cells, thereby accelerating neighboring cell death and promoting ferroptosis propagation. FOXK1 was phosphorylated by PKCβII and then facilitated the expression and secretion of Galectin-13 during ferroptotic cell death. Correlation analysis and functional analysis revealed that ferroptosis propagation ability was a previously unrecognized determinant of ferroptosis sensitivity in human cancer cells. A synthetic Galectin-13 mimetic peptide was shown to strongly enhance the sensitivity of tumors to the imidazole ketone erastin, radiotherapy and immunotherapy by boosting ferroptosis. In particular, cancer stem cells were vulnerable to the combination of Galectin-13 mimetic peptide and ferroptosis inducers. Our study provides new insights into ferroptosis propagation and highlights novel strategies for targeting ferroptosis to treat tumors.
... In addition, cell death in cultured cells treated with ferroptosis-inducing agents occurred in wave-like patterns with spatiotemporal characteristics distinct from other forms of cell death 27,28 . Platelet activation factor (PAF) and derivatives have been implicated in this process 29 . However, the use of drugs to induce or block ferroptosis, potentially affecting all cells in the population, has limited the study of the spread of ferroptosis across cells. ...
Ferroptosis is a lytic, iron-dependent form of regulated cell death characterized by excessive lipid peroxidation and associated with necrosis spread in diseased tissues through unknown mechanisms. Using a novel optogenetic system for light-driven ferroptosis induction via degradation of the anti-ferroptotic protein GPX4, we show that lipid peroxidation and ferroptotic death can spread to neighboring cells through their closely adjacent plasma membranes. Ferroptosis propagation is dependent on cell distance and completely abolished by disruption of α-catenin-dependent intercellular contacts or by chelation of extracellular iron. Remarkably, bridging cells with a lipid bilayer or increasing contacts between neighboring cells enhances ferroptosis spread. Reconstitution of iron-dependent spread of lipid peroxidation between pure lipid, contacting liposomes provides evidence for the physicochemical mechanism involved. Our findings support a model in which iron-dependent lipid peroxidation propagates across proximal plasma membranes of neighboring cells, thereby promoting the transmission of ferroptotic cell death with consequences for pathological tissue necrosis spread.
... Diabetic kidney disease (DKD), the most severe microvascular complication of diabetes, is the leading cause of end-stage renal disease (ESRD) and is related to markedly increased morbidity and mortality of cardiovascular disease worldwide [1][2][3]. The prominent pathological manifestations of DKD are glomerular hypertrophy, thickening of the basement membrane and mesangial expansion, which are caused by mesangial cell remolding, eventually leading to glomerulosclerosis [4]. ...
Background
Diabetic kidney disease (DKD) is the leading cause of end-stage renal disease (ESRD) globally, presenting a significant therapeutic challenge. Extracellular vesicles (EVs) from mesenchymal stem cells (MSCs) have emerged as promising therapeutic agents. This study explored the therapeutic effects and mechanisms of EVs derived from human placental mesenchymal stem cells (hP-MSCs) on DKD.
Methods
EVs were isolated from cultured hP-MSCs and administered to streptozotocin (STZ)-induced diabetic mice and high glucose–treated glomerular mesangial cells. The therapeutic impact of EVs was assessed through histological analysis and biochemical assays. miR-99b-5p expression in EVs and its role in modulating the mechanistic target of rapamycin (mTOR)/autophagy pathway were examined via western blotting and RT‒qPCR.
Results
Treatment with hP-MSC-derived EVs significantly alleviated renal fibrosis and improved renal function in DKD models. These EVs were enriched with miR-99b-5p, which targeted and inhibited mTOR signaling, thereby increasing autophagic activity and reducing cellular proliferation and extracellular matrix accumulation in renal tissues.
Conclusions
hP-MSC-derived EVs can mitigate renal injury in DKD by modulating the miR-99b-5p/mTOR/autophagy pathway. These findings suggest a potential cell-free therapeutic strategy for managing DKD.
... Renal tubules do not sensitize to necrotic apoptosis after selective removal of FAD or caspase-8, and the RIPK1 inhibitor necrostatin-1 (Nec-1) cannot protect freshly isolated tubules from hypoxic damage (25). An interesting feature of ferroptosis is that it can rapidly propagate between RTECs in a wave-like manner, which can be explained by the diffusion of the NADPH gradient formed by the reduced redox capacity within injured RTECs through intercellular junctions (26,27). Notably, ferroptosis drives the accumulation of injured RTECs, which underlie renal interstitial fibers (14,28). ...
Background
Severe renal ischemia and reperfusion injury (IRI) progresses to renal interstitial fibrosis (RIF) with limited therapeutic strategies. Although ferrptosis and macrophage polarization both play important roles in this model, their specific pathogenesis and interactions have not been elucidated. Therefore, we aimed to explore the mechanisms by which ferrotosis occurs in renal tubular epithelial cells (RTECs) and ferroptotic cell-derived exosomes induce macrophage polarization in IRI-related RIF model.
Methods
In vivo, C57BL/6J mice were randomly divided into four groups: sham group, ischemia and reperfusion (IR) group, IR + Ferrostatin-1 (Fer-1) group, and IR +ATF3 knockdown (ATFKD) group. In vitro, RTECs were divided into control (CON) group, hypoxia/reoxygenation (HR) group, HR +Fer-1 group, HR + siRNA-ATF3 (siATF3) group.
Result
Compared with the sham group, the IR group showed more severe kidney injury in HE staining, more collagen fibers in Masson staining, and higher α-SMA expression levels in immunohistochemistry. Total iron and MDA content increased while GSH content decreased. The IR group had more significant mitochondrial damage and higher PTGS2 and TFRC mRNA levels than those in the sham group. Compared with the IR group, the above indexes were all alleviated in the IR+Fer-1 or IR+ATF3KD groups. In addition, the protein expressions of ATF3, Nrf2 and HO-1 in the IR group were increased than those in sham group. Compared with the IR group, ATF3 expressions in the IR+Fer-1 or IR+ATF3KD groups were decreased, and the protein contents of Nrf2 and HO-1 were further increased. Moreover, there were higher levels of M2 markers (Arg1, TGF-β and IL-10 mRNA) in the IR group than those in the sham group, and lower levels in the IR+Fer-1 group or in the IR+ATF3KD group compared with the IR group. The results of in vitro experiment are consistent with those of in vivo experiment. Mechanistically, the release of exosomes carrying miR-1306-5p by the HR group promoted more M2 macrophage.
Conclusion
ATF3 might accelerate the ferroptosis by inhibiting Nrf2/ARE pathway, and exosomes from ferroptotic cells reduced the M1/M2 macrophage ratio, promoting fibrosis.
... Recent studies have found that the occurrence of ferroptosis in renal tubular cells is an important pathological change in AKI, and promoting ferroptosis of renal tubular epithelial cells can expedite the progression of AKI (30). On the contrary, inhibition of ferroptosis in renal tubular epithelial cells can significantly protect against AKI (31)(32)(33)(34). However, the specific mechanism of ferroptosis in renal tubular epithelial cells in AKI necessitates further studies. ...
Introduction
Cisplatin is a widely used chemotherapeutic agent prescribed to treat solid tumors. However, its clinical application is limited because of cisplatin- induced nephrotoxicity. A known complication of cisplatin is acute kidney injury (AKI). Deletion polymorphisms of GSTM1 and GSTT1, members of the glutathione S-transferase family, are common in humans and are presumed to be associated with various kidney diseases. However, the specific roles and mechanisms of GSTM1 and GSTT1 in cisplatin induced AKI remain unclear.
Methods
To investigate the roles of GSTM1 and GSTT1 in cisplatin-induced AKI, we generated GSTM1 and GSTT1 knockout mice using CRISPR-Cas9 technology and assessed their kidney function under normal physiological conditions and cisplatin treatment. Using ELISA kits, we measured the levels of oxidative DNA and protein damage, along with MDA, SOD, GSH, and the GSH/GSSG ratio in wild-type and GSTM1/GSTT1 knockout mice following cisplatin treatment. Additionally, oxidative stress levels and the expression of ferroptosis-related proteins in kidney tissues were examined through Western blotting, qPCR, immunohistochemistry, and immunofluorescence techniques.
Results
Here, we found that GSTT1 and GSTM1 were downregulated in the renal tubular cells of AKI patients and cisplatin-treated mice. Compared with WT mice, Gstm1/Gstt1-DKO mice were phenotypically normal but developed more severe kidney dysfunction and exhibited increased ROS levels and severe ferroptosis after injecting cisplatin.
Discussion
Our study revealed that GSTM1 and GSTT1 can protect renal tubular cells against cisplatin-induced nephrotoxicity and ferroptosis, and genetic screening for GSTM1 and GSTT1 polymorphisms can help determine a standard cisplatin dose for cancer patients undergoing chemotherapy.
... Therefore, the inception and progression of ferroptosis are an integrated outcome of numerous dysregulated metabolic pathways under the control of both inducible and inhibitory molecules. Additionally, ferroptosis has been Ivyspring International Publisher observed to exacerbate several pathological processes and human diseases, including obesity, type 2 diabetes (T2D) and its complications, and non-alcoholic fatty liver disease (NAFLD), by further disrupting metabolic homeostasis, amplifying the propagation of ferroptotic death signals, and initiating inflammatory responses [10][11][12][13]. Consequently, the implementation of ferroptosis-based therapies holds immense promise in catalyzing remarkable strides in the field of disease treatment. ...
... Hence, it is essential to identify ferroptosis signaling types and their mode of action for comprehending the progression of ferroptosis. Interestingly, platelet-activating factor (PAF) and PAF-like phospholipids, which are released by ferroptotic cells and actively internalized by adjacent cells via endocytosis, induce membrane rupture and subsequent cellular demise, exemplifying the propagation of ferroptotic death signals [12]. EVs have recently been found to be an attractive transmitter for ferroptosis signals [125]. ...
Ferroptosis, an iron-dependent form of regulated cell death, is emerging as a crucial regulator of human physiology and pathology. Increasing evidence showcases a reciprocal relationship between ferroptosis and dysregulated metabolism, propagating a pathogenic vicious cycle that exacerbates pathology and human diseases, particularly metabolic disorders. Consequently, there is a rapidly growing interest in developing ferroptosis-based therapeutics. Therefore, a comprehensive understanding of the intricate interplay between ferroptosis and metabolism could provide an invaluable resource for mechanistic insight and therapeutic development. In this review, we summarize the important metabolic substances and associated pathways in ferroptosis initiation and progression, outline the cascade responses of ferroptosis in disease development, overview the roles and mechanisms of ferroptosis in metabolic diseases, introduce the methods for ferroptosis detection, and discuss the therapeutic perspectives of ferroptosis, which collectively aim to illustrate a comprehensive view of ferroptosis in basic, translational, and clinical science.
... It has become evident that the extensive necrotic regions observed during tubular necrosis are derived from cells that have succumbed to ferroptosis, which might initiate cell death propagation [58][59][60]. Recent studies have revealed that platelet-activating factor (PAF), PAF-like phospholipids (PAF-LPLs) and human proximal tubular epithelial cell-derived small extracellular vesicles mediate synchronized tubular ferroptosis [61,62]. Ni et al. observed a notable upregulation of ferroptosis-associated genes in AKI patients [63]. ...
Kidney diseases are significant global public health concern, with increasing prevalence and substantial economic impact. Developing novel therapeutic approaches are essential for delaying disease progression and improving patient quality of life. Cell death signifying the termination of cellular life, could facilitate appropriate bodily development and internal homeostasis. Recently, regulated cell death (RCD) forms such as ferroptosis, characterized by iron-dependent lipid peroxidation, has garnered attention in diverse renal diseases and other pathological conditions. This review offers a comprehensive examination of ferroptosis, encompassing an analysis of the involvement of iron and lipid metabolism, the System Xc⁻/glutathione/glutathione peroxidase 4 signaling, and additional associated pathways. Meanwhile, the review delves into the potential of targeting ferroptosis as a therapeutic approach in the management of acute kidney injury (AKI), chronic kidney disease (CKD), diabetic nephropathy, and renal tumors. Furthermore, it emphasizes the significance of ferroptosis in the transition from AKI to CKD and further accentuates the potential for repurposing drug and utilizing traditional medicine in targeting ferroptosis-related pathways for clinical applications. The integrated review provides valuable insights into the role of ferroptosis in kidney diseases and highlights the potential for targeting ferroptosis as a therapeutic strategy.
... As expected, SeNPs supplementation inhibited H/R-induced lipid ROS accumulation in HK-2 cells (Fig. 2H). Ferroptotic cells exhibite mitochondrial dysfunction, including the decreased mitochondrial membrane potential [32]. Using the JC-1 probe, we found that the mitochondrial membrane potential declined upon H/R treatment, indicating the loss of mitochondrial function, which could be markedly inhibited by SeNPs (Fig. 2I). ...
Acute kidney injury (AKI) is closely related to lysosomal dysfunction and ferroptosis in renal tubular epithelial cells (TECs), for which effective treatments are urgently needed. Although selenium nanoparticles (SeNPs) have emerged as promising candidates for AKI therapy, their underlying mechanisms have not been fully elucidated. Here, we investigated the effect of SeNPs on hypoxia/reoxygenation (H/R)-induced ferroptosis and lysosomal dysfunction in TECs in vitro and evaluated their efficacy in a murine model of ischemia/reperfusion (I/R)-AKI. We observed that H/R-induced ferroptosis was accompanied by lysosomal Fe ²⁺ accumulation and dysfunction in TECs, which was ameliorated by SeNPs administration. Furthermore, SeNPs protected C57BL/6 mice against I/R-induced inflammation and ferroptosis. Mechanistically, we found that lysosomal Fe ²⁺ accumulation and ferroptosis were associated with the excessive activation of NCOA4-mediated ferritinophagy, a process mitigated by SeNPs through the upregulation of X-box binding protein 1 (XBP1). Downregulation of XBP1 promoted ferritinophagy and partially counteracted the protective effects of SeNPs on ferroptosis inhibition in TECs. Overall, our findings revealed a novel role for SeNPs in modulating ferritinophagy, thereby improving lysosomal function and attenuating ferroptosis of TECs in I/R-AKI. These results provide evidence for the potential application of SeNPs as therapeutic agents for the prevention and treatment of AKI.
... Tripartite motif-containing 21 (TRIM21) exacerbated IRI-induced AKI by ubiquitylating GPX4 to promote ferroptosis [111]. Furthermore, knockdown or pharmacological inhibition of PAF-acetylhydrolase (II) (PAFAH2) increases platelet-activating factor (PAF) production, enhances synchronized ferroptosis, and exacerbates IRI-AKI [112]. After renal IRI, ubiquitin-specific protease 7 (USP7) inhibits fragile X mental retardation 1 (FMR1) expression and accelerates ferroptosis by promoting TANKbinding kinase 1 (TBK1) ubiquitination and DNA methyltransferase 1 (DNMT1) deubiquitination [113]. ...
Acute kidney injury (AKI) is one of the most common and severe clinical renal syndromes with high morbidity and mortality. Ferroptosis is a form of programmed cell death (PCD), is characterized by iron overload, reactive oxygen species accumulation, and lipid peroxidation. As ferroptosis has been increasingly studied in recent years, it is closely associated with the pathophysiological process of AKI and provides a target for the treatment of AKI. This review offers a comprehensive overview of the regulatory mechanisms of ferroptosis, summarizes its role in various AKI models, and explores its interaction with other forms of cell death, it also presents research on ferroptosis in AKI progression to other diseases. Additionally, the review highlights methods for detecting and assessing AKI through the lens of ferroptosis and describes potential inhibitors of ferroptosis for AKI treatment. Finally, the review presents a perspective on the future of clinical AKI treatment, aiming to stimulate further research on ferroptosis in AKI.
Graphical abstract
... These processes ultimately induce ferroptosis (24). Furthermore, a phospholipase present in the cytoplasm, namely platelet-activating factor (PAF)-acetylhydrolase (II), specifically inhibits short-chain fatty acid oxidation, interfering with the cell's redox capacity and blocking the aggregation of oxidized phospholipids such as PAF; this leads to membrane rupture, inhibiting cell ferroptosis (25). Acetyl-coenzyme A (CoA) of the mevalonate pathway inhibits ferroptosis by triggering the NADPH-FSP1-CoQ10 pathway via the regulation of CoQ10 synthesis. ...
Ferroptosis, a regulated form of cell death, is intricately linked to iron‑dependent lipid peroxidation. Recent evidence strongly supports the induction of ferroptosis as a promising strategy for treating cancers resistant to conventional therapies. A key player in ferroptosis regulation is ferroptosis suppressor protein 1 (FSP1), which promotes cancer cell resistance by promoting the production of the antioxidant form of coenzyme Q10. Of note, FSP1 confers resistance to ferroptosis independently of the glutathione (GSH) and glutathione peroxidase‑4 pathway. Therefore, targeting FSP1 to weaken its inhibition of ferroptosis may be a viable strategy for treating refractory cancer. This review aims to clarify the molecular mechanisms underlying ferroptosis, the specific pathway by which FSP1 suppresses ferroptosis and the effect of FSP1 inhibitors on cancer cells.
