Induction of ferroptosis selectively eliminates senescent tubular cells

Liao, Chieh Ming; Wulfmeyer, Vera Christine; Chen, Rongjun; Erlangga, Zulrahman; Sinning, Julius; Mäßenhausen, Anne von; Sörensen-Zender, Inga; Beer, Kristina; Vietinghoff, Sibylle von; Haller, Hermann; Linkermann, Andreas; Melk, Anette; Schmitt, Roland

doi:10.1111/ajt.17102

Cited by 22 publications

(12 citation statements)

References 51 publications

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“…We next explored senolytic agents to efficiently eliminate senescent angiosarcoma cells. To this end, we employed three recently identified senolytic agents, ABT-263 (inhibitor of anti-apoptotic BCL-2), BPTES (inhibitor of glutaminase 1), and RSL3 (inhibitor of GPX4 ferroptosis regulator) (Chang et al, 2016, Johmura et al, 2021, Liao et al, 2022, Zhu et al, 2016).…”

Section: Resultsmentioning

confidence: 99%

“…To eliminate senescent cells derived from chemotherapeutic drug treatment of angiosarcoma cells, we examined three senolytic agents: ABT-263 (Chang et al, 2016, Zhu et al, 2016), BPTES (Johmura et al, 2021), and RSL3 (Liao et al, 2022). We observed that all three agents could eliminate senescent angiosarcoma cells to varying degrees; ISO-HAS-B angiosarcoma cells treated by cisplatin exhibit enhanced vulnerability to the senolytic agents compared to untreated control cells, although ABT-263 was more effective than BPTES and RSL3 ( Figure 4b-c ).…”

Section: Discussionmentioning

confidence: 99%

“…Although ABT-263 is reported to have platelet toxicity, recent advances have been made to reduce the toxicity of ABT-263 by conjugating it with cleavable galactose or by encapsulating it with galacto-oligosaccharides, allowing this senolytic agent to be preferentially activated in senescent cells (Gonzalez-Gualda et al, 2020, Munoz-Espin et al, 2018. Moreover, there are other types of senolytic agents, such as BPTES (inhibitor of glutaminase 1) and RSL3 (inhibitor of GPX4 ferroptosis regulator) (Johmura et al, 2021, Liao et al, 2022. However, the optimal combination of chemo-senolytic agents remains to be explored for respective cancers.…”

Section: Introductionmentioning

confidence: 99%

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Chemo-senolytic therapeutic potential against angiosarcoma

Wang,

Chung,

Yoshioka

et al. 2023

Preprint

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Angiosarcoma is an aggressive soft-tissue sarcoma with a poor prognosis. Chemotherapy for this cancer typically employs paclitaxel, one of the taxanes (genotoxic drugs), although it has a limited effect due to chemoresistance for prolonged treatment. Here we examine a new angiosarcoma treatment approach that combines chemotherapeutic and senolytic agents. We first find that the chemotherapeutic drugs, cisplatin and paclitaxel, efficiently induce cellular senescence of angiosarcoma cells. Subsequent treatment with a senolytic agent, ABT-263, eliminates senescent cells through the activation of the apoptotic pathway. In addition, expression analysis indicates that senescence-associated secretory phenotype (SASP) genes are activated in senescent angiosarcoma cells and that ABT-263 treatment eliminates senescent cells expressing genes in the type-I interferon (IFN-I) pathway. Moreover, we show that cisplatin treatment alone requires a high dose to remove angiosarcoma cells, whereas a lower dose of cisplatin is sufficient to induce senescence, followed by the elimination of senescent cells by senolytic treatment. This study sheds light on a potential therapeutic strategy against angiosarcoma by combining a relatively low dose of cisplatin with the ABT-263 senolytic agent, which can help ease the deleterious side effects of chemotherapy.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Chemo-senolytic therapeutic potential against angiosarcoma

Wang,

Chung,

Yoshioka

et al. 2023

Preprint

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“…Recently, it was reported that Nupr1 plays an inhibitory role in ferroptosis, an iron‐dependent, lipid‐peroxidation‐driven, regulated cell death (Huang et al, 2021). Liao et al (2022) found that ferroptosis induction selectively eliminated senescent kidney tubular epithelial cells. More recently, it has been reported that there are sex differences in response to ferroptosis (Ide et al, 2022).…”

Section: Discussionmentioning

confidence: 99%

Nupr1 deficiency downregulates HtrA1, enhances SMAD1 signaling, and suppresses age‐related bone loss in male mice

Murayama

Hirata

Shiraki

et al. 2023

Journal Cellular Physiology

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Nuclear protein 1 (NUPR1) is a stress-induced protein activated by various stresses, such as inflammation and oxidative stress. We previously reported that Nupr1 deficiency increased bone volume by enhancing bone formation in 11-week-old mice. Analysis of differentially expressed genes between wild-type (WT) and Nupr1knockout (Nupr1-KO) osteocytes revealed that high temperature requirement A 1 (HTRA1), a serine protease implicated in osteogenesis and transforming growth factor-β signaling was markedly downregulated in Nupr1-KO osteocytes. Nupr1 deficiency also markedly reduced HtrA1 expression, but enhanced SMAD1 signaling in in vitro-cultured primary osteoblasts. In contrast, Nupr1 overexpression enhanced HtrA1 expression in osteoblasts, suggesting that Nupr1 regulates HtrA1 expression, thereby suppressing osteoblastogenesis. Since HtrA1 is also involved in cellular senescence and age-related diseases, we analyzed aging-related bone loss in Nupr1-KO mice. Significant spine trabecular bone loss was noted in WT male and female mice during 6−19 months of age, whereas aging-related trabecular bone loss was attenuated, especially in Nupr1-KO male mice. Moreover, cellular senescencerelated markers were upregulated in the osteocytes of 6−19-month-old WT male mice but markedly downregulated in the osteocytes of 19-month-old Nupr1-KO male mice. Oxidative stress-induced cellular senescence stimulated Nupr1 and HtrA1 expression in in vitro-cultured primary osteoblasts, and Nupr1 overexpression enhanced p16 ink4a expression in osteoblasts. Finally, NUPR1 expression in osteocytes isolated from the bones of patients with osteoarthritis was correlated with age.Collectively, these results indicate that Nupr1 regulates HtrA1-mediated osteoblast differentiation and senescence. Our findings unveil a novel Nupr1/HtrA1 axis, which may play pivotal roles in bone formation and age-related bone loss.

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“…Abnormal iron metabolism can cause renal tubular dysfunction and adversely affect the maintenance of renal function. For example, Liao et al found that iron deposition in the tubular epithelial cells of patients with DKD may produce nephrotoxicity and damage the kidneys [ 9 ]. Li et al found that the concentrations of malondialdehyde (MDA) and 4-hydroxytryptamine (4-HNE) increased in the DKD model, and ROS increased significantly in renal cortical proximal tubule epithelial cells (HK2) under a high glucose environment.…”

Section: Introductionmentioning

confidence: 99%

Identification of Markers for Diagnosis and Treatment of Diabetic Kidney Disease Based on the Ferroptosis and Immune

Liu

et al. 2022

Oxidative Medicine and Cellular Longevity

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Background. In advanced diabetic kidney disease (DKD), iron metabolism and immune dysregulation are abnormal, but the correlation is not clear. Therefore, we aim to explore the potential mechanism of ferroptosis-related genes in DKD and their relationship with immune inflammatory response and to identify new diagnostic biomarkers to help treat and diagnose DKD. Methods. Download data from gene expression omnibus (GEO) database and FerrDb database, and construct random forest tree (RF) and support vector machine (SVM) model to screen hub ferroptosis genes (DE-FRGs). We used consistent unsupervised consensus clustering to cluster DKD samples, and enrichment analysis was performed by Gene Set Variation Analysis (GSVA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) and then assessed immune cell infiltration abundance using the single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT algorithms. Ferroptosis scoring system was established based on the Boruta algorithm, and then, core compounds were screened, and binding sites were predicted by Coremine Medical database. Results. We finally established a 7-gene signature (DUSP1, PRDX6, PEBP1, ZFP36, GABARAPL1, TSC22D3, and RGS4) that exhibited good stability across different datasets. Consistent clustering analysis divided the DKD samples into two ferroptosis modification patterns. Meanwhile, autophagy and peroxisome pathways and immune-related pathways can participate in the regulation of ferroptosis modification patterns. The abundance of immune cell infiltration differs significantly across patterns. Further, molecular docking results showed that the core compound could bind to the protein encoded by the core gene. Conclusions. Our findings suggest that ferroptosis modification plays a crucial role in the diversity and complexity of the DKD immune microenvironment, and the ferroptosis score system can be used to effectively verify the relationship between ferroptosis and immune cell infiltration in DKD patients. Kaempferol and quercetin may be potential drugs to improve the immune and inflammatory mechanisms of DKD by affecting ferroptosis.

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Induction of ferroptosis selectively eliminates senescent tubular cells

Cited by 22 publications

References 51 publications

Chemo-senolytic therapeutic potential against angiosarcoma

Chemo-senolytic therapeutic potential against angiosarcoma

Nupr1 deficiency downregulates HtrA1, enhances SMAD1 signaling, and suppresses age‐related bone loss in male mice

Identification of Markers for Diagnosis and Treatment of Diabetic Kidney Disease Based on the Ferroptosis and Immune

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