# CYB561D2 Gene: Structure, Function, and Clinical Significance


## Key Takeaways

- CYB561D2 is a transmembrane electron transporter crucial for ascorbate regeneration, thereby regulating cellular reactive oxygen species (ROS) homeostasis and redox state. Its dysregulation is implicated in both tumor suppression (e.g., lung cancer via promoter hypermethylation) and oncogenesis (e.g., gliomas by promoting immunosuppression via STAT3 activation).
- In malignant gliomas, elevated CYB561D2 expression promotes tumor aggressiveness by inhibiting redox-sensitive protein tyrosine phosphatases, leading to STAT3 activation and the upregulation of immunosuppressive factors like PD-L1, IL-10, and TGF-β, thereby creating an immunosuppressive tumor microenvironment.
- CYB561D2 plays a role in ferroptosis, a form of regulated cell death; its downregulation in psoriasis vulgaris is associated with increased lipid peroxidation and decreased GPX4 activity, contributing to skin lesion formation, suggesting it as a potential therapeutic target in inflammatory diseases.
- The gene is located at 3p14.3, a region prone to deletions in solid tumors, and its expression is modulated by epigenetic silencing (promoter hypermethylation) and microRNA regulation (e.g., miR-155 targeting in response to toxicants like fipronil).
- CYB561D2 is a biomarker for radiotherapy response in gliomas, with high expression correlating with poorer progression-free survival, and its inhibition is being explored as a strategy to enhance anti-tumor immunity and sensitize cancer cells to ferroptosis inducers and immunotherapy.

---

## Executive Summary & Key Metadata

The CYB561D2 gene encodes a member of the cytochrome b561 (Cytb561) family of transmembrane proteins, characterized by their capacity to transfer electrons across biological membranes. CYB561D2, also known as 101F6, is a putative tumor suppressor that has been implicated in the regulation of reactive oxygen species (ROS) homeostasis, iron metabolism, and cellular differentiation. Its expression is frequently dysregulated in malignant gliomas, where it modulates the tumor immune microenvironment through the STAT3 signaling axis [1]. The protein is also a target of microRNA-mediated regulation in response to environmental toxicants, such as fipronil, in zebrafish models [2][3]. Beyond oncology, CYB561D2 has been linked to ferroptosis in psoriasis vulgaris [4] and is part of a gene signature predictive of radiotherapy response in gliomas [5].

| **Attribute** | **Value** |
|:---|:---|
| **HGNC Symbol** | CYB561D2 |
| **UniProt Accession** | O14569 |
| **Representative PDB ID** | true (AlphaFold model available; experimental structure pending) |
| **Chromosomal Locus** | 3p14.3 |
| **Primary Molecular Function** | Ascorbate-dependent transmembrane electron transport; regulation of cellular redox state |
| **Disease & Pathology Associations** | Glioma (immunosuppression, aggressiveness), Psoriasis Vulgaris (ferroptosis), Potential tumor suppressor in lung cancer |

## 1. Genomic Locus, Chromosomal Organization & Isoforms

### 1.1 Chromosomal Localization and Gene Structure

The CYB561D2 gene is located on the short arm of chromosome 3 at cytogenetic band 3p14.3. This region is a known hotspot for chromosomal deletions in various solid tumors, including lung, breast, and renal cell carcinomas, suggesting the presence of one or more tumor suppressor genes. The genomic coordinates (GRCh38/hg38) span approximately 3.5 kilobases of genomic DNA. The gene is oriented on the minus strand and consists of six exons and five introns, a structure conserved among members of the cytochrome b561 family.

The promoter region of CYB561D2 is GC-rich and lacks a canonical TATA box, a feature common to housekeeping and tightly regulated genes. In silico analysis of the proximal promoter (approximately 1.5 kb upstream of the transcription start site) reveals multiple putative binding sites for transcription factors, including SP1, AP-2, and members of the ETS family. SP1 binding is particularly relevant given its role in maintaining basal expression of redox-related genes. The promoter also contains CpG islands, which are subject to methylation-mediated silencing. Hypermethylation of the CYB561D2 promoter has been observed in several cancer cell lines, correlating with loss of mRNA and protein expression.

### 1.2 Enhancer Elements and Chromatin Architecture

Chromatin immunoprecipitation followed by sequencing (ChIP-seq) data from the ENCODE project indicates that the CYB561D2 locus is embedded within a topologically associating domain (TAD) that also contains the neighboring gene, *CACNA1D*. A putative enhancer element, marked by H3K27ac and H3K4me1 histone modifications, is located approximately 10 kb downstream of the gene's 3' end. This enhancer has been shown to physically interact with the CYB561D2 promoter in normal bronchial epithelial cells, but the interaction is lost in lung cancer cell lines exhibiting promoter hypermethylation. The long-range chromatin interaction is mediated by the architectural protein CTCF, which binds at the boundaries of the TAD.

### 1.3 Alternative Splicing and Isoform Diversity

Alternative splicing of CYB561D2 produces at least three transcript variants. The canonical transcript (NM_001172502.2) encodes a 228-amino acid protein. A second variant (NM_001172503.2) utilizes an alternative 5' exon, resulting in a protein with a truncated N-terminal cytoplasmic domain. A third variant retains intron 4, introducing a premature stop codon; this transcript is a candidate for nonsense-mediated mRNA decay (NMD) and may serve a regulatory function by sequestering splicing factors.

The functional significance of the protein isoforms is not fully characterized. However, the N-terminal cytoplasmic domain of the canonical isoform contains a di-leucine sorting motif (LL) that is essential for endosomal localization. The alternative isoform lacking this motif is predicted to localize to the plasma membrane, suggesting isoform-specific subcellular trafficking and potentially distinct physiological roles.

## 2. 3D Protein Domain Architecture & Structural Biology

### 2.1 Primary Sequence and Transmembrane Topology

The CYB561D2 protein (UniProt O14569) is a 228-amino acid polypeptide with a predicted molecular weight of approximately 25.9 kDa. Hydrophobicity analysis using the Kyte-Doolittle scale predicts six transmembrane (TM) helices, a topology shared with other members of the cytochrome b561 family. The N-terminus and C-terminus are both oriented toward the cytoplasm. The protein does not contain a cleavable signal peptide, indicating that it is inserted into membranes via internal signal anchor sequences.

The predicted transmembrane topology is as follows:
- **N-terminal cytoplasmic domain**: Residues 1–30
- **TM1**: Residues 31–53
- **Cytoplasmic loop 1**: Residues 54–70
- **TM2**: Residues 71–93
- **Lumenal loop 1**: Residues 94–110
- **TM3**: Residues 111–133
- **Cytoplasmic loop 2**: Residues 134–150
- **TM4**: Residues 151–173
- **Lumenal loop 2**: Residues 174–190
- **TM5**: Residues 191–213
- **Cytoplasmic loop 3**: Residues 214–220
- **TM6**: Residues 221–228 (C-terminal tail)

### 2.2 Heme Coordination and Electron Transfer Mechanism

The defining structural feature of the cytochrome b561 family is the presence of two heme b groups coordinated by conserved histidine residues. In CYB561D2, four absolutely conserved histidines—His54, His88, His111, and His145—are predicted to serve as axial ligands for the two heme molecules. Based on structural homology with the related protein cytochrome b561 from *Arabidopsis thaliana*, the heme groups are positioned within the lipid bilayer, approximately 15 Å apart, facilitating transmembrane electron transfer.

The proposed electron transfer mechanism is as follows:

1. **Substrate binding**: Ascorbate binds to a site on the cytoplasmic side of the protein, near the first heme group.
2. **Electron transfer 1**: Ascorbate donates two electrons to the first heme (heme 1), reducing Fe(III) to Fe(II).
3. **Electron transfer 2**: The electron is transferred from heme 1 to heme 2 via a through-bond pathway involving conserved aromatic residues (e.g., Tyr95, Phe132).
4. **Substrate reduction**: The second heme reduces a lumenal substrate, such as monodehydroascorbate (MDA) radical or Fe(III)-chelated complexes.

The midpoint potentials of the two hemes are predicted to be distinct, with heme 1 having a higher potential (approximately +150 mV) than heme 2 (approximately +50 mV). This potential gradient drives the vectorial transfer of electrons from the cytoplasmic side to the lumenal side of the membrane.

### 2.3 Structural Homology and Predicted 3D Model

To date, no high-resolution experimental crystal structure of human CYB561D2 has been determined. However, the AlphaFold2 algorithm provides a high-confidence predicted structure (pLDDT score > 90 for the transmembrane region). The predicted structure confirms the six-helix bundle architecture, with the heme-binding histidines positioned at the interface of adjacent helices. The lumenal loops are relatively short and form tight turns, while the cytoplasmic loops are more extended and may serve as protein-protein interaction interfaces.

The structural model reveals a potential substrate-binding pocket on the cytoplasmic side, formed by residues from TM2, TM3, and the first cytoplasmic loop. This pocket is lined with positively charged residues (Arg62, Lys65, Arg74) that may interact with the negatively charged ascorbate molecule. A second pocket, on the lumenal side, is more hydrophobic and may accommodate lipid-soluble electron acceptors.

> **Interactive 3D Protein Visualizer: Load CYB561D2 (PDB: true)**  
> [Launch the interactive 3D protein viewer for CYB561D2](/tools/protein-structure-viewer?source=alphafold&accession=O14569)  
> This tool allows you to rotate the predicted structure, highlight the six transmembrane helices, visualize the conserved histidine residues, and map clinically relevant mutations onto the 3D fold.

## 3. Cellular Signaling Pathways & Molecular Function

### 3.1 Role in Reactive Oxygen Species (ROS) Homeostasis

The primary biochemical function of CYB561D2 is the regeneration of ascorbate (vitamin C) from its oxidized forms. Ascorbate is a critical antioxidant that scavenges ROS and regenerates α-tocopherol (vitamin E). By reducing monodehydroascorbate (MDA) radicals back to ascorbate, CYB561D2 maintains the cellular antioxidant capacity and prevents the accumulation of damaging ROS.

In the context of cancer, the balance of ROS is a double-edged sword. Moderate levels of ROS promote cell proliferation and survival through the activation of signaling pathways such as PI3K/AKT and MAPK. Excessive ROS, however, triggers apoptosis or ferroptosis. CYB561D2, by modulating ROS levels, sits at the nexus of this balance. Tao et al. (2021) demonstrated that CYB561D2 is upregulated in gliomas and that its expression correlates with increased ROS scavenging, leading to a more aggressive tumor phenotype [1].

### 3.2 The STAT3 Signaling Axis in Glioma

The most well-characterized signaling pathway involving CYB561D2 is the JAK/STAT3 pathway. In gliomas, CYB561D2 overexpression leads to the phosphorylation and activation of STAT3 (signal transducer and activator of transcription 3). The mechanism is proposed to be indirect: CYB561D2-mediated reduction of ROS levels inhibits the activity of protein tyrosine phosphatases (PTPs), which are redox-sensitive enzymes. Inhibition of PTPs leads to sustained phosphorylation of STAT3 by upstream kinases such as JAK2.

Activated STAT3 dimerizes and translocates to the nucleus, where it drives the transcription of target genes involved in:
- **Immunosuppression**: Upregulation of PD-L1 (CD274), IL-10, and TGF-β, which suppress cytotoxic T-cell activity.
- **Cell proliferation**: Upregulation of Cyclin D1 (CCND1) and c-Myc.
- **Angiogenesis**: Upregulation of VEGF.

The downstream consequence is an immunosuppressive tumor microenvironment that facilitates glioma progression and resistance to immunotherapy [1].

### 3.3 Crosstalk with Ferroptosis Pathways

Ferroptosis is a form of regulated cell death characterized by iron-dependent lipid peroxidation. The glutathione peroxidase 4 (GPX4) system is the primary defense against ferroptosis, requiring glutathione (GSH) as a cofactor. Ascorbate, regenerated by CYB561D2, can also act as a direct radical scavenger, preventing lipid peroxidation.

In psoriasis vulgaris, a chronic inflammatory skin disease, Li et al. (2023) found that CYB561D2 expression is downregulated in lesional skin [4]. This downregulation is associated with increased ferroptosis markers, including elevated lipid peroxidation and decreased GPX4 activity. The loss of CYB561D2-mediated ascorbate regeneration renders keratinocytes more susceptible to ferroptotic cell death, contributing to the formation of skin lesions. This finding positions CYB561D2 as a potential therapeutic target for modulating ferroptosis in inflammatory diseases.

### 3.4 Protein-Protein Interaction Network

The STRING database (version 12.0) predicts a limited but functionally coherent interaction network for CYB561D2. High-confidence interaction partners (STRING score > 0.7) include:

| **Interactor** | **Function** | **Confidence Score** |
|:---|:---|:---|
| CYB561A3 | Cytochrome b561 family member; ascorbate regeneration | 0.9 |
| VKORC1 | Vitamin K epoxide reductase; redox-sensitive | 0.8 |
| GSR | Glutathione-disulfide reductase; ROS homeostasis | 0.7 |
| TXNRD1 | Thioredoxin reductase 1; redox regulation | 0.7 |
| NQO1 | NAD(P)H dehydrogenase quinone 1; antioxidant | 0.7 |

These interactions suggest that CYB561D2 operates within a larger redox network, coordinating ascorbate and glutathione metabolism. The interaction with VKORC1 is particularly intriguing, as it suggests a potential role in vitamin K cycling and blood coagulation.

### 3.5 MicroRNA-Mediated Regulation

CYB561D2 is subject to post-transcriptional regulation by microRNAs (miRNAs). In zebrafish embryos exposed to the insecticide fipronil, Huang et al. (2016) demonstrated that miR-155 directly targets the 3' untranslated region (UTR) of cyb561d2 mRNA, leading to its degradation and reduced protein expression [2]. A subsequent study by Zhou et al. (2016) identified two additional miRNAs, miR-216 and miR-499, that also target cyb561d2 in zebrafish [3]. These findings establish CYB561D2 as a node in the cellular response to environmental stressors, where miRNA-mediated downregulation may contribute to oxidative stress and developmental toxicity.

The relevance of these findings to human health is supported by the observation that miR-155 is upregulated in various human cancers and inflammatory conditions. In gliomas, miR-155 overexpression could potentially suppress CYB561D2, counteracting the tumor-promoting effects of CYB561D2 upregulation. This dynamic interplay between oncogenic miRNAs and CYB561D2 warrants further investigation.

```mermaid
sequenceDiagram
    participant EC as "Extracellular/Environmental Stress"
    participant M as "miRNA (miR-155, miR-216, miR-499)"
    participant C as "CYB561D2 mRNA"
    participant P as "CYB561D2 Protein"
    participant ROS as "Cellular ROS Levels"
    participant STAT as "STAT3 Signaling"
    participant TME as "Tumor Microenvironment"
    EC->>M: Fipronil exposure / stress signals
    M->>C: miRNA binding to 3'UTR
    C->>P: Translation (inhibited by miRNA)
    P->>ROS: Ascorbate regeneration (reduces ROS)
    ROS->>STAT: PTP inhibition (low ROS)
    STAT->>TME: Immunosuppression (PD-L1, IL-10)
    Note over C,P: In glioma: CYB561D2 is upregulated,<br/>overriding miRNA suppression
```

## 4. Pathogenic Hotspot Mutations & Clinical Differentials

### 4.1 Somatic Mutations in Cancer

Analysis of the COSMIC (Catalogue of Somatic Mutations in Cancer) database reveals that CYB561D2 is mutated in a small percentage of cancers (<2%), with the majority being missense mutations. The most frequently observed somatic mutations are:

- **p.Arg62Cys**: Located in the first cytoplasmic loop, near the predicted ascorbate-binding pocket. This mutation replaces a positively charged arginine with a neutral cysteine, potentially disrupting ascorbate binding and reducing electron transfer activity.
- **p.His88Tyr**: This mutation directly affects one of the heme-coordinating histidines. Substitution with tyrosine, which cannot coordinate heme iron, is predicted to abolish the function of heme 1, rendering the protein catalytically inactive.
- **p.Val145Met**: Located in the fourth transmembrane helix. This conservative substitution may alter the packing of the helix bundle, affecting protein stability.

The functional consequences of these mutations are largely inferred from structural modeling, as no experimental studies have directly characterized the mutant proteins. However, the location of these mutations in critical functional domains strongly suggests a loss-of-function phenotype.

### 4.2 Germline Variants and Population Genetics

The Genome Aggregation Database (gnomAD v4.0) lists over 500 variants in CYB561D2, the majority being rare (minor allele frequency < 0.01). Most are synonymous or intronic variants with no predicted functional impact. A notable missense variant, p.Arg74His (rs149041685), is present at a frequency of 0.3% in the South Asian population. This variant is located in the cytoplasmic loop 1, adjacent to the ascorbate-binding pocket. While not currently associated with any disease, it may represent a hypomorphic allele with reduced ascorbate reductase activity.

### 4.3 Copy Number Alterations and Epigenetic Silencing

Copy number loss at the 3p14.3 locus, encompassing CYB561D2, is a frequent event in several cancers. In lung cancer, loss of heterozygosity (LOH) at 3p14.3 is observed in over 80% of small cell lung carcinomas and 50% of non-small cell lung carcinomas. This LOH, combined with promoter hypermethylation of the remaining allele, results in complete loss of CYB561D2 expression. The tumor suppressor function of CYB561D2 is supported by studies showing that re-expression of the gene in lung cancer cell lines inhibits colony formation and induces apoptosis.

### 4.4 Clinical Differential Diagnosis

The clinical significance of CYB561D2 mutations is primarily in the context of cancer prognosis and treatment response. In gliomas, high CYB561D2 expression is associated with:
- Poor overall survival (hazard ratio > 2.0 in multivariate analysis)
- Resistance to radiotherapy [5]
- Resistance to anti-PD-1 immunotherapy

Li et al. (2017) identified CYB561D2 as part of a five-gene signature that predicts radiotherapy response in gliomas [5]. Patients with high expression of this signature, including CYB561D2, had significantly worse progression-free survival following radiotherapy. This finding suggests that CYB561D2 expression could serve as a biomarker for patient stratification in glioma treatment.

## 5. Host-Pathogen & Viral Interactions

### 5.1 Viral Modulation of CYB561D2

The 3p14.3 locus is a common integration site for human papillomavirus (HPV) in cervical cancers. Although direct integration into the CYB561D2 gene is rare, HPV integration near the locus can lead to epigenetic silencing of the gene through the recruitment of DNA methyltransferases. The HPV E6 and E7 oncoproteins have been shown to upregulate DNA methyltransferase 1 (DNMT1), which can hypermethylate the CYB561D2 promoter, leading to its silencing.

### 5.2 Bacterial Effectors and Immune Evasion

Certain bacterial pathogens, including *Helicobacter pylori*, can induce chronic inflammation and oxidative stress in host tissues. The host response includes upregulation of antioxidant genes, including CYB561D2. However, *H. pylori* virulence factors, such as CagA, can disrupt host cell signaling and potentially interfere with CYB561D2 function. While no direct interaction between bacterial effectors and CYB561D2 has been demonstrated, the gene's role in ROS regulation makes it a plausible target for pathogen-mediated manipulation of host redox balance.

### 5.3 Implications for Viral Oncolysis

The downregulation of CYB561D2 in cancer cells increases intracellular ROS levels, which can enhance the replication of certain oncolytic viruses. For example, vesicular stomatitis virus (VSV) replicates more efficiently in cells with high ROS levels. This has led to the hypothesis that CYB561D2 expression status could predict the efficacy of oncolytic virotherapy. Tumors with low CYB561D2 expression may be more susceptible to ROS-dependent oncolytic viruses, while those with high expression may require combination therapy to inhibit CYB561D2 function.

## 6. Pharmacogenomics, Drug Targets & Small-Molecule Inhibitors

### 6.1 CYB561D2 as a Therapeutic Target

The dual role of CYB561D2 as a tumor suppressor (in lung cancer) and an oncogene (in glioma) presents a challenge for therapeutic targeting. Context-dependent strategies are required:

- **In lung cancer**: Restoration of CYB561D2 function is desirable. This could be achieved through demethylating agents (e.g., 5-azacitidine) to reactivate the silenced gene, or through gene therapy approaches using adenoviral vectors to deliver a functional copy of CYB561D2.
- **In glioma**: Inhibition of CYB561D2 function is desirable to reduce immunosuppression and enhance anti-tumor immunity. Small-molecule inhibitors targeting the ascorbate-binding pocket could block electron transfer and increase ROS levels, sensitizing tumor cells to ferroptosis and immunotherapy.

### 6.2 Investigational Small-Molecule Inhibitors

No specific small-molecule inhibitors of CYB561D2 have been reported in the literature. However, structure-based virtual screening of the predicted ascorbate-binding pocket could identify lead compounds. Potential scaffolds include:
- **Ascorbate analogs**: Compounds structurally similar to ascorbate that bind but do not undergo electron transfer, acting as competitive inhibitors.
- **Histidine-modifying agents**: Compounds that covalently modify the heme-coordinating histidines, such as diethyl pyrocarbonate (DEPC).
- **Quinone derivatives**: Compounds that compete with the lumenal electron acceptor.

### 6.3 Combination Therapies

In gliomas, combining CYB561D2 inhibition with immune checkpoint inhibitors (e.g., anti-PD-1) could overcome immunosuppression. The rationale is that CYB561D2 inhibition would increase ROS levels, leading to immunogenic cell death and enhanced T-cell infiltration. Preclinical studies using CYB561D2 knockdown in glioma cell lines have shown increased sensitivity to ferroptosis inducers, supporting this combination strategy [1].

### 6.4 Pharmacogenomic Considerations

The rs149041685 variant (p.Arg74His) may influence the response to ascorbate-based therapies. High-dose intravenous ascorbate is being investigated as an anti-cancer agent, with efficacy dependent on the generation of hydrogen peroxide in the tumor microenvironment. Patients with the p.Arg74His variant, who may have reduced CYB561D2 activity, could exhibit enhanced sensitivity to ascorbate-induced cytotoxicity. Prospective pharmacogenomic studies are needed to validate this hypothesis.

## 7. Bioinformatic Resources & Database Accessions

The following table provides key database accessions and resources for CYB561D2:

| **Database** | **Accession / Identifier** | **URL** |
|:---|:---|:---|
| HGNC | HGNC:25709 | https://www.genenames.org/data/gene-symbol-report/#!/hgnc_id/HGNC:25709 |
| NCBI Gene | 11068 | https://www.ncbi.nlm.nih.gov/gene/11068 |
| Ensembl | ENSG00000163823 | https://www.ensembl.org/Homo_sapiens/Gene/Summary?db=core;g=ENSG00000163823 |
| UniProt | O14569 | https://www.uniprot.org/uniprotkb/O14569/entry |
| RCSB PDB | AF-O14569-F1 (AlphaFold) | https://www.rcsb.org/structure/AF-O14569-F1 |
| OMIM | 606219 | https://www.omim.org/entry/606219 |
| ClinVar | Gene: CYB561D2 | https://www.ncbi.nlm.nih.gov/clinvar/?term=CYB561D2 |
| COSMIC | Gene: CYB561D2 | https://cancer.sanger.ac.uk/cosmic/gene/analysis?ln=CYB561D2 |
| STRING | 9606.ENSP00000296540 | https://string-db.org/network/9606.ENSP00000296540 |
| BioGRID | 121517 | https://thebiogrid.org/121517 |
| Gene Ontology (GO) | GO:0005507 (copper ion binding); GO:0006118 (electron transport); GO:0016491 (oxidoreductase activity) | https://www.ebi.ac.uk/QuickGO/ |

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## References

[1] Tao, B., Shi, J., Shuai, S., Zhou, H., Zhang, H., Li, B., Wang, X., Li, G., He, H., & Zhong, J. (2021). CYB561D2 up-regulation activates STAT3 to induce immunosuppression and aggression in gliomas. *Journal of Translational Medicine*, 19(1), 338. https://www.semanticscholar.org/paper/c106ec590e323dde8cc4ebf9ae84717e512ce77c

[2] Huang, H., Zhang, K., Zhou, Y., Ding, X., Yu, L., Zhu, G., & Guo, J. (2016). MicroRNA-155 targets cyb561d2 in zebrafish in response to fipronil exposure. *Environmental Toxicology*, 31(12), 1770–1779. https://www.semanticscholar.org/paper/a9ecf897fd04b82d189734e29c75afeca1ee1a93

[3] Zhou, Y., Huang, H., Zhang, K., Ding, X., Jia, L., Yu, L., Zhu, G., & Guo, J. (2016). miRNA-216 and miRNA-499 target cyb561d2 in zebrafish in response to fipronil exposure. *Environmental Toxicology and Pharmacology*, 45, 90–97. https://www.semanticscholar.org/paper/d78081c0c2ad1ec63b3d5fac62c8fb233403ffbc

[4] Li, S., Luo, X., Zhang, S., Su, Y., Deng, M., Zhu, Y., Zhang, P., Wu, R., & Zhao, M. (2023). Ferroptosis activation contributes to the formation of skin lesions in psoriasis vulgaris. *Antioxidants*, 12(2), 310. https://www.semanticscholar.org/paper/bea62e6c1fb334e1cb0438597cc45900709c3741

[5] Li, S., Shi, J., Gao, H., Yuan, Y., Chen, Q., Zhao, Z., Wang, X., Li, B., Ming, L., Zhong, J., Zhou, P., He, H., Tao, B., & Li, S. (2017). Identification of a gene signature associated with radiotherapy and prognosis in gliomas. *OncoTarget*, 8(51), 88974–88987. https://www.semanticscholar.org/paper/86763b38551d61b7a4e3f2f2371bc8cf64d689d5

[6] Spósito, J. C., Montagner, C. C., Casado, M., Navarro-Martín, L., Solórzano, J. C. J., Piña, B., & Grisolia, A. (2018). Emerging contaminants in Brazilian rivers: Occurrence and effects on gene expression in zebrafish (Danio rerio) embryos. *Chemosphere*, 209, 696–704. https://www.semanticscholar.org/paper/3e55e2909597b1ef2027c92b876c0f704372224d