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All issues pointed by the reviewers were adequately addressed and revised manuscript is acceptable now.
[# PeerJ Staff Note - this decision was reviewed and approved by Sonia Oliveira, a PeerJ Section Editor covering this Section #]
No Comments
No Comments
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The authors have addressed the comments satisfactorily and acknowledged the limitations acceptably. I would appreciate the editor’s consideration and acceptance of the manuscript.
Plese address issues pointed by all reviewers and revise manuscript accordingly.
. The authors don’t review any new exciting aspects of PCD or Ferroptosis; instead, it’s a review of a few reviews.
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Before starting the comments, the first question to the authors is whether this review provides anything further than
1, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10577123/
2, https://www.nature.com/articles/s41392-020-00428-9
General comments:
The review needs careful language editing
Introduction
The introduction should provide a good overview of ferroptosis and can be enhanced with a few additions to make it more comprehensive.
1. Specify the common diseases linked to ferroptosis, such as neurodegenerative diseases (e.g., Alzheimer’s and Parkinson’s), cancer, and cardiovascular diseases. This will help contextualize its relevance.
2. It is essential to emphasize the distinctive biochemical pathways of ferroptosis (e.g., the GPX4-GSH pathway and lipid ROS generation that set it apart from other types of cell death, like apoptosis or necrosis.
3. Mention emerging therapeutic strategies targeting ferroptosis, such as developing ferroptosis inducers or inhibitors, and any potential clinical trials, if applicable.
4. Since this is a review, briefly mention the specific aspects of ferroptosis the paper will cover (e.g., signaling pathways, biomarkers, therapeutic targets) and why they are crucial for advancing the field.
Keywords: “Ferroptosis, Mechanism, Inducer, Inhabitor, Disease” What do the authors mean by Mechanism? Disease is one of the vaguest terms anyone can use as a keyword. “Inhabitor” is a new term.
Minor errors
a. “Autophage, apoptosis, and necroptosis have been discovered followed.” is grammatically incorrect and lacks clarity. Autophagy is a cellular process, not a type of cell death, and the sentence does not flow logically.
b. The sentence “This provides insights into the pathogenesis and treatment of the disease.” is vague. Which disease? Be specific and avoid using non-descriptive terms like "the disease."
c. “This study will focus on the role of ferroptosis in common diseases and treatment.”: Instead of ending with a broad statement, conclude with a concise summary of what the study aims to achieve and why it is significant in the field.
The review
It acknowledges the diseases and their connection with ferroptosis, but all with standards such as the Role of Ferroptosis in Pathology: Ferroptosis is a common form of regulated cell death across all mentioned diseases. Glutathione peroxidase 4 (GPX4), reactive oxygen species (ROS), lipid peroxidation, and iron metabolism dysregulation are repeatedly highlighted as central players in ferroptosis. Dysregulation of iron homeostasis is a recurring theme. Protective and Therapeutic Strategies: Ferroptosis inhibitors, such as ferrostatin-1, liproxstatin-1, and vitamin E, are consistently mentioned as potential therapeutic agents that can mitigate the damage caused by ferroptosis in different disease models
For the abstract, using "common disease" is broad. It would be better to provide examples, such as cardiovascular diseases (e.g., heart disease, stroke), respiratory diseases (e.g., asthma, chronic obstructive pulmonary disease), and infectious diseases (e.g., the common cold, flu), which would make the abstract more relevant to a wider audience.
There’s a typo in the keywords: "Ferroptosis, Mechanism, Inducer, Inhabitor, Disease." It should be "inhibitor."
Overall, regarding the main context:
Some sentences could be simplified or broken into smaller parts for better readability.
It would help to use better transitions between the different diseases or studies being discussed, making it easier to follow the flow of ideas.
Make sure the acronyms (e.g., ROS, MDA, GSH, IBD, I/R, etc.) are clearly defined upon first use. Some of them are common terms in biology, but not all readers may be familiar with them.
For the section on survey methodology, consider the following improvement suggestions:
It’s essential to explain why these specific keywords were used. For instance, you could state that the terms were chosen to capture a comprehensive view of ferroptosis across various organ systems and immune cell types that are relevant to the scope of your study. This would make your methodology more robust and show that the search was systematic.
Use consistent formatting for terms and ensure they are presented in lowercase or uppercase as appropriate (e.g., "neutrophils" instead of "Neutrophils").
By addressing these points, your methodology will be clearer and more justified for the reader.
For the section on Ferroptosis and intestinal disease:
In line 57, you mention that ferroptosis can be induced by I/R injury, but it's important to clearly explain why ferroptosis is a central mechanism in this context. Providing more background on why ferroptosis might be more relevant than other forms of cell death (like apoptosis or necrosis) would strengthen your argument.
The paragraph provides interesting findings (e.g., lipin-1 overexpression [lines 74-75], acetaminophen-induced ferroptosis, and GPX4 protection [lines 78-80]) but lacks sufficient mechanistic detail. Why does lipin-1 overexpression lead to ferroptosis? How do GPX4 and vitamin E prevent ferroptosis?
For the section on Ferroptosis and liver disease:
The section on liver fibrosis and hepatic stellate cells is a bit brief (lines 86-87). Since fibrosis is a chronic process, the potential for targeting ferroptosis for therapeutic intervention should be more clearly stated. What role does ferroptosis play compared to other pathways in the progression of fibrosis?
For the section on Ferroptosis and kidney disease:
To improve clarity, consider splitting the section into acute kidney injury and chronic kidney disease to better address the distinct mechanisms and therapeutic approaches related to ferroptosis in each condition.
The section on AKI references studies showing the protective effects of ferroptosis inhibitors but lacks a detailed discussion of the underlying mechanisms of how ferroptosis occurs during ischemia-reperfusion injury or hypoxia.
The discussion on diabetic nephropathy feels a bit disjointed, with some parts focusing on the role of iron overload and others on the role of GPX4, without clear transitions.
For the section on Ferroptosis and cerebrovascular disease:
The paragraph mentions both ischemic and hemorrhagic strokes but does not adequately differentiate the mechanisms of ferroptosis in these two types.
The transition from discussing stroke to Alzheimer's disease feels abrupt. The connection between cerebrovascular diseases and neurodegeneration could be emphasized better to illustrate the relationship between these conditions.
The mention of the GPX4 knockout study in mice is important, but it could benefit from more detail. What specific cognitive dysfunctions were observed, and how does GPX4 relate to ferroptosis? A clearer explanation of the implications of knocking out GPX4 in the context of ferroptosis would enhance understanding.
For the section on Ferroptosis and cardiovascular disease:
The mention of COQ10 as a treatment is valuable, but the paragraph could benefit from additional context regarding its clinical implications and how it specifically targets ferroptosis.
For the section on Ferroptosis and immune disease:
The paragraph mentions several studies and their findings but lacks a detailed explanation of the mechanisms by which ferroptosis influences immune cell functions.
The paragraph includes information about how infection can induce ferroptosis, but it would be more effective to integrate this information within the context of the immune cell response to infection.
For the section on Ferroptosis and tumors:
The section discussing CD8+ T cells and their influence on SLC3A2 and SLC7A11 could be clearer. It might also benefit from a more explicit description of these proteins' roles in GSH synthesis.
The mention of ACSL4 could benefit from additional detail. Its role in migration, proliferation, and invasion is significant, but the mechanisms behind these effects are unclear.
For the section on the induction and treatment of ferroptosis:
The explanation of how erastin induces ferroptosis could be enhanced by clarifying its mechanisms.
The mention of copper promoting iron apoptosis could be confusing without context.
For the conclusion:
Consider adding a sentence that highlights the potential for ferroptosis research to revolutionize therapeutic strategies.
The phrase "wide range of diseases" is broad. Specifying a few disease types (e.g., cancer, neurodegenerative diseases, etc.) could provide more context.
no comments
Overall, the manuscript is well written, though with some grammatical errors. I would recommend some edits and proofread before publication.
In terms of novelty, I am still struggling to find the novelty in this review since there are so many reviews on Ferroptosis in the past few years, for example
1. Li, J., Cao, F., Yin, Hl. et al. Ferroptosis: past, present and future. Cell Death Dis 11, 88 (2020). https://doi.org/10.1038/s41419-020-2298-2
2. Zhang, C., Liu, X., Jin, S. et al. Ferroptosis in cancer therapy: a novel approach to reversing drug resistance. Mol Cancer 21, 47 (2022). https://doi.org/10.1186/s12943-022-01530-y
3. Chen, Z., Wang, W., Abdul Razak, S.R. et al. Ferroptosis as a potential target for cancer therapy. Cell Death Dis 14, 460 (2023). https://doi.org/10.1038/s41419-023-05930-w
However, I would not reject the manuscript based on this point alone. I wonder if the author might want to add a paragraph discussing the future of research for Ferroptosis or why targeting Ferroptosis is promising, to make the manuscript stands out from the rest.
Another major concern that I have is the organization. It is my personal taste to have summary tables for these types of reviews so that the reader can navigate the text more easily.
Major Comments
1. The section ‘Ferroptosis and Tumour’ is too broad, in my opinion, since each cancer has a specific pathogenesis. Maybe the author should focus on only specific types of cancers that are known to be related to ferroptosis, such as liver or lung cancer.
2. I think if the author included an overview of the molecular mechanism of Ferroptosis (Canonical GPX4 vs. Lipid Metabolism vs. Iron Metabolism), it would give the reader a framework to think around this problem and make the manuscript easier to read.
3. In terms of organization, it would be easier for readers to read if the author listed all the Ferroptosis inducers and inhibitors in a table, with details on what type of disease these perturbations are mentioned in the literature.
Minor Comments
1. Line 66 -> What is DFO? Can the author spell this out
2. Line 103 -> What does this sentence mean? : ‘ability to propagate in a wavy manner through the cell population’
This a review article, that includes only published and reviewed materials.
I have no comment on this section.
The is a review article. This section does not apply.
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