A double-edged sword with a therapeutic target: iron and ferroptosis in immune regulation

Ni, Shuo; Yuan, Yin; Song, Shangdao; Li, Xin

doi:10.1093/nutrit/nuac071

Cited by 7 publications

(8 citation statements)

References 99 publications

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“…33 Iron is an important factor in EMT, metastasis, and immunomodulation in human cancers. 4,34,35 STEAP3, an iron reductase, was associated with the infiltration of immune cells in hepatocellular carcinoma and induced PD-L2 expression. 36 It may induce the formation of a tumor immune microenvironment in ccRCC.…”

Section: Discussionmentioning

confidence: 99%

“…Iron metabolism is closely related to cancer development 3 and subtle changes can influence the local microenvironment and function of immune cells. 4 Several researchers have reported the role of the sixtransmembrane epithelial antigen of the prostate (STEAP) family, a type of iron metabolism-associated protein in different cancers. 5,6 STEAP family member 3 (STEAP3) performs a pivotal function in iron uptake as a metalloreductase by reducing ferric iron to ferrous iron.…”

Section: Introductionmentioning

confidence: 99%

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Six‐transmembrane epithelial antigen of prostate 3 (STEAP3) is a potential prognostic biomarker in clear cell renal cell carcinoma that correlates with M2 macrophage infiltration and epithelial–mesenchymal

Wei

Zhao

et al. 2023

Cancer Reports

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BackgroundThe six‐transmembrane epithelial antigen of the prostate 3 (STEAP3) is a metalloreductase, which is essential for iron uptake. Existing literature has shown that STEAP3 may perform an important role in the onset and progression of tumors. Nonetheless, a complete pan‐cancer investigation of the prognostic significance and immune properties of STEAP3 is currently unavailable.AimsAs part of our investigation into the possible functions of STEAP3 in malignancies, we conducted a comprehensive analysis to examine the prognostic value and immune features of STEAP3 in human pan‐cancer.Methods and ResultsR and Cytoscape programs were applied to analyze and visualize the data. The expression of STEAP3 in both cell lines and tissues was measured utilizing a variety of approaches. Using the shRNA knockdown technique, we tested the viability of the A498 and 786‐O cell lines and validated their functions. Both CCK‐8 and transwell assays were conducted to estimate cell proliferation and invasion. The expression of STEAP3 was substantially elevated and was shown to be linked to prognosis in the majority of malignancies, notably in clear cell renal cell carcinoma (ccRCC). In addition, the expression of STEAP3 was shown to have a strong correlation with immune infiltrates, which in turn triggered the recruitment and polarization of M2 macrophages in ccRCC. The protein STEAP3 shows promise as a predictor of responses to immune‐checkpoint blockade (ICB) therapy. Positive links between STEAP3 and the epithelial‐mesenchymal transition (EMT), the p53 pathway, and the immune‐associated pathways were also found in the enrichment analysis. Our results illustrated that the STEAP3 expression level was substantially elevated in ccRCC tissues and suggested that it could stimulate EMT in ccRCC by downregulating CDH1.ConclusionIn a diverse range of cancers, STEAP3 might serve as a biomarker for determining the prognosis as well as a predictor of immunotherapy responsiveness. STEAP3 is a novel biological marker for determining prognosis, and it also performs a remarkable function in the promotion of tumor growth in ccRCC by enhancing invasion and EMT, as well as by triggering the recruitment and polarization of M2 macrophages.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Six‐transmembrane epithelial antigen of prostate 3 (STEAP3) is a potential prognostic biomarker in clear cell renal cell carcinoma that correlates with M2 macrophage infiltration and epithelial–mesenchymal

Wei

Zhao

et al. 2023

Cancer Reports

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“…8,51 Since single-cell sequencing analysis revealed that the key FRGs are also expressed in immune cells, while a close association between ferroptosis and immune cell function and activity has been reported in other biological environments, the immune infiltration analyses were further performed in our study to explore the cross-talks between ferroptosis and immune cells in SMI. 28,52,53 We estimated the relative proportions of infiltrating immune cells in each heart sample from the GSE79962 dataset using the CIBERSORT algorithm, as shown in Figure 8A, while the clustered heatmap of infiltrating immune cells shows the differences between control and septic hearts (Figure 8B). M2 macrophage was found at the highest proportion among immune cells in these heart samples, and it was lower in septic hearts (0.35 ± 0.08 vs 0.37 ± 0.08, septic hearts vs control), corresponding to a higher proportion of M1 macrophage (0.02 ± 0.04 vs 0.005 ± 0.01, septic hearts vs control) However, M1 and M2 macrophage did not show significance due to large individual differences (p > 0.05).…”

Section: Immune Infiltration Analysesmentioning

confidence: 99%

“…Furthermore, we performed immune infiltration correlation analyses of identified key FRGs in septic hearts given the tight association between SMI, ferroptosis, and immune infiltration. 8,[26][27][28] Finally, we predicted potential ferroptosis-modulating drugs for SMI based on the drug-target correlation of key FRGs, and performed molecular docking for further exploration.…”

Section: Introductionmentioning

confidence: 99%

Exploring Dysregulated Ferroptosis-Related Genes in Septic Myocardial Injury Based on Human Heart Transcriptomes: Evidence and New Insights

Zou¹,

Hu²,

Zhao³

et al. 2023

JIR

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Introduction: Sepsis is currently a common condition in emergency and intensive care units, and is defined as life-threatening organ dysfunction caused by a dysregulated host response to infection. Cardiac dysfunction caused by septic myocardial injury (SMI) is associated with adverse prognosis and has significant economic and human costs. The pathophysiological mechanisms underlying SMI have long been a subject of interest. Recent studies have identified ferroptosis, a form of programmed cell death associated with iron accumulation and lipid peroxidation, as a pathological factor in the development of SMI. However, the current understanding of how ferroptosis functions and regulates in SMI remains limited, particularly in the absence of direct evidence from human heart. Methods: We performed a sequential comprehensive bioinformatics analysis of human sepsis cardiac transcriptome data obtained through the GEO database. The lipopolysaccharide-induced mouse SMI model was used to validate the ferroptosis features and transcriptional expression of key genes. Results: We identified widespread dysregulation of ferroptosis-related genes (FRGs) in SMI based on the human septic heart transcriptomes, deeply explored the underlying biological mechanisms and crosstalks, followed by the identification of key functional modules and hub genes through the construction of protein-protein interaction network. Eight key FRGs that regulate ferroptosis in SMI, including HIF1A, MAPK3, NOX4, PPARA, PTEN, RELA, STAT3 and TP53, were identified, as well as the ferroptosis features. All the key FRGs showed excellent diagnostic capability for SMI, part of them was associated with the prognosis of sepsis patients and the immune infiltration in the septic hearts, and potential ferroptosis-modulating drugs for SMI were predicted based on key FRGs. Conclusion:This study provides human septic heart transcriptome-based evidence and brings new insights into the role of ferroptosis in SMI, which is significant for expanding the understanding of the pathobiological mechanisms of SMI and exploring promising diagnostic and therapeutic targets for SMI.

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“…Iron is a transitional metal abundantly present and indispensable trace element in the human body, which participates in numerous important physiological and biochemical functions, including cell division, DNA repair and death [10]. Iron overload is the main source of active oxygen, a key participation factor for ferroptosis, and emerging studies have shown that iron overload is closely related to RCC occurrence, especially clear cell renal cell carcinoma (ccRCC).…”

Section: Iron Metabolismmentioning

confidence: 99%

Research Progress on Ferroptosis as a Therapeutic Strategy in Renal Cell Carcinoma

Liu

Bai

Cui³

et al. 2022

ann urol oncol

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Renal cell carcinoma (RCC) is a common type of kidney cancer in adults and constitutes approximately 90% of all renal malignancies. Although advancements have been made in the treatment of RCC, the 5 -year survival rate is still low, and new treatment modalities are still required. Ferroptosis is an iron-dependent programmed cell death caused by the accumulation of lipid peroxide products. Recent studies revealed the involvement of ferroptosis metabolism, lipid peroxidation, and System XC-GSH-GPX4 shafts as major mechanisms closely related to RCC progression. Nanoparticles in combination with small molecular ferroptosis induction agents have the advantages of solubility, targeted enhancement, low systemic toxicity, controllable drug control, and synergy advantage in emerging combination therapies. In the future, it is possible to be used in nano treatment. The relationship between ferroptosis-related mechanisms and RCC progression and its role in the treatment could provide novel treatment strategies for patients with advance-stage RCC.

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A double-edged sword with a therapeutic target: iron and ferroptosis in immune regulation

Cited by 7 publications

References 99 publications

Six‐transmembrane epithelial antigen of prostate 3 (STEAP3) is a potential prognostic biomarker in clear cell renal cell carcinoma that correlates with M2 macrophage infiltration and epithelial–mesenchymal

Six‐transmembrane epithelial antigen of prostate 3 (STEAP3) is a potential prognostic biomarker in clear cell renal cell carcinoma that correlates with M2 macrophage infiltration and epithelial–mesenchymal

Exploring Dysregulated Ferroptosis-Related Genes in Septic Myocardial Injury Based on Human Heart Transcriptomes: Evidence and New Insights

Research Progress on Ferroptosis as a Therapeutic Strategy in Renal Cell Carcinoma

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