Ferroptosis in Myocardial Fibrosis: Mechanisms and Therapeutic Insights

Round 1

Reviewer 1 Report

The review provides a well-structured and clearly written overview of the relation between ferroptosis and myocardial fibrosis, covering key aspects of iron, glutathione, and lipid metabolism as well as the etiology and molecular mechanism of cardiac remodeling. It might be considered by the authors that a brief discussion of inflammatory pathways (potentially including activation of MMPs) could further enhance the completeness of the review. Overall, the manuscript represents a solid and valuable contribution to the field.

The reference lists are up to date, relevant and adequately support the manuscript. But please note that: In ref 97, the correct citation should be: .Zhan Y, Zhou Y, Zhang C, Zhai Z, Yang Y, Liu X. Transferrin receptor knockdown attenuates atrial fibrillation by inhibiting cardiomyocyte ferroptosis and atrial fibrosis. Exp Anim. 2025 Jul 11;74(3):348-361. Also, the ref 157 has been retracted.

 

A few  editorial corrections are needed to polish the manuscript.

The figures provide a very good visual summary of the main mechanisms discussed in the main subsections related to ferroptosis. However, the smallest font size used in the figures is clearly too small, rendering the text largely illegible. In a Figures 2,  the smallest font is completely unreadable. The use of a handwritten-style font further compromises readability.
Furthermore, it would be beneficial to include full definitions of all abbreviations directly in the figure legends. Although the abbreviations are explained in the main text and listed at the end of the manuscript, providing them below the figures would greatly improve readability.

Author Response

Dear Reviewer：

Thank you very much for the opportunity to revise our manuscript titled “Ferroptosis in Myocardial Fibrosis: Mechanisms and Therapeutic Insights” (Manuscript Number: antioxidants-4045664). We would also like to express our gratitude to the reviewers for their time and valuable feedback. We have carefully addressed all the comments and suggestions provided, which have greatly helped improve the quality and clarity of our work.

Please find below our point-by-point responses to the reviewers’ comments, along with the corresponding revisions made to the manuscript. We believe that these revisions have enhanced the manuscript, and we hope that the revised version meets the journal’s standards for publication.

Comment 1: In ref 97, the correct citation should be: Zhan Y, Zhou Y, Zhang C, Zhai Z, Yang Y, Liu X. Transferrin receptor knockdown attenuates atrial fibrillation by inhibiting cardiomyocyte ferroptosis and atrial fibrosis. Exp Anim. 2025 Jul 11;74(3):348-361. Also, the ref 157 has been retracted.

Response: We sincerely appreciate you catching this critical issue. We have corrected the citation information for reference 97 in accordance with PubMed standard format. For the retracted reference 157, we have deleted the corresponding citation in the main text and replaced it with another relevant and high-quality study, while also updating the reference list.

Comment 2: The smallest font size used in the figures is clearly too small, rendering the text largely illegible. In Figure 2, the smallest font is completely unreadable. The use of a handwritten-style font further compromises readability.

Response: We have enlarged all fonts and symbols in Figure 1 and Figure 2, ensuring a minimum font size of 8 pt, ensuring compliance with journal publication standards. Additionally, we have improved the image resolution and optimized line thickness and contrast, significantly enhancing clarity for both printing and screen reading.

Comment 3: Furthermore, it would be beneficial to include full definitions of all abbreviations directly in the figure legends. Although the abbreviations are explained in the main text and listed at the end of the manuscript, providing them below the figures would greatly improve readability.

Response: We added a legend to Figure 1 and Figure 2, in which a dedicated section titled "Abbreviation" is included to list the full forms of each abbreviation, ensuring that readers can understand the content of the figures without referring to the main text.

We sincerely thank all reviewers for their constructive feedback, which has substantially strengthened our manuscript.We look forward to hearing from you and are happy to make any further revisions as needed.

Sincerely,

Lin Li

Reviewer 2 Report

This review discusses the role of ferroptosis, an iron-dependent lipid peroxidation–driven form of regulated cell death, in the initiation and progression of myocardial fibrosis (MF). By synthesizing studies published between 2020 and 2025, the authors outline how disturbances in iron metabolism, lipid peroxidation, glutathione/redox imbalance, and dysregulated ferroptosis-related pathways (including Nrf2) contribute to MF. The review highlights ferroptosis-targeted modulation as a promising therapeutic avenue for mitigating cardiac fibrosis.

The manuscript addresses an important topic and is generally well written; however, several points require clarification or further refinement. My detailed comments are provided below.

1. The figure legends should be expanded for clarity and improved readability.
2. On page 6, line 228, the authors state that “the interaction between p53 and Nrf2 involves cell cycle effects [69]”. This statement requires further clarification. Providing a 1–2 sentence mechanistic explanation would improve clarity and scientific completeness.
3. In Figure 1, the authors refer to “Ferritinophagy” in the caption, but in the main text, they consistently use “fer autophagy”. This inconsistency may confuse readers. The authors should use a single term throughout the manuscript and ensure that Figure 1, its caption, and the text employ the same terminology.
4. The review does not discuss ncRNA-mediated and systems-level regulation of ferroptosis; a recent systems biology study (PMID: 39846637) may provide useful complementary insight.

See my comments on "Major comments."

Author Response

Dear Reviewer：

Thank you very much for the opportunity to revise our manuscript titled “Ferroptosis in Myocardial Fibrosis: Mechanisms and Therapeutic Insights” (Manuscript Number: antioxidants-4045664). We would also like to express our gratitude to the reviewers for their time and valuable feedback. We have carefully addressed all the comments and suggestions provided, which have greatly helped improve the quality and clarity of our work.

Please find below our point-by-point responses to the reviewers’ comments, along with the corresponding revisions made to the manuscript. We believe that these revisions have enhanced the manuscript, and we hope that the revised version meets the journal’s standards for publication.

Comment 1: The figure legends should be expanded for clarity and improved readability.

Response: We have enlarged the text and symbols in Figure 1 and Figure 2. Additionally, we have improved the image resolution and optimized the line thickness and contrast, significantly enhancing the clarity for both printing and screen reading. Furthermore, we have added legends to Figure 1 and Figure 2 to briefly describe the content of each subplot, and included a dedicated section titled "Abbreviation" that lists the full names of each abbreviation, ensuring that readers can understand the chart content without referring to the main text.

Comment 2: On page 6, line 228, the authors state that “the interaction between p53 and Nrf2 involves cell cycle effects [69]”. This statement requires further clarification. Providing a 1–2 sentence mechanistic explanation would improve clarity and scientific completeness.

Response: We have added a mechanistic explanation after the sentence (see the red-highlighted portion in lines 230-234 on page 7) : "Additionally, Jose E et al. discovered that p53 and Nrf2 also exhibit synergistic regula-tion at the cellular cycle level. Both agents repair damage by activating antioxidant de-fenses and arresting the cell cycle at low concentrations of H₂O₂; however, under high levels of oxidative stress, this synergistic effect is suppressed, and cells instead initiate the apoptotic pathway. "

Comment 3: In Figure 1, the authors refer to “Ferritinophagy” in the caption, but in the main text, they consistently use “fer autophagy”. This inconsistency may confuse readers. The authors should use a single term throughout the manuscript and ensure that Figure 1, its caption, and the text employ the same terminology.

Response: We have uniformly corrected "Ferritinophagy" in Figure 1 to "fer autophagy" as used in the main text, and conducted a terminology consistency check throughout the entire document to ensure that all terms are presented in a uniform format across all figures, figure captions, and the main text.

Comment 4: The review does not discuss ncRNA-mediated and systems-level regulation of ferroptosis; a recent systems biology study (PMID: 39846637) may provide useful complementary insight.

Response: We greatly appreciate you bringing this important study to our attention. We have added lines 530-537 on page 14 (highlighted in red) in the Discussion section to specifically elaborate on:" In addition, recent studies have revealed that non-coding RNAs constitute an important regulatory network in the ferroptosis-oxidative stress-inflammation axis: miR-130b-3p both promotes GPX4 expression and inhibits ACSL4 activity, thereby reducing the production of L-ROS and suppressing ferroptosis. The overexpression of miR-214-3p leads to both the downregulation of p53 and the upregulation of SLC7A11 and GPX4, thereby inhibiting ferroptosis. Unlike traditional single-target interventions, non-coding RNAs exhibit the unique advantage of multi-pathway synergistic regulation, opening up new avenues for the modulation of ferroptosis. "

Comment 5: The English could be improved to more clearly express the research.

Response: We have commissioned a professional medical editing company to perform native language polishing on the full text, with a focus on optimizing sentence structure, logical coherence, and terminology accuracy. The polishing certificate has been submitted as an attachment. No substantive changes have been made to the academic content.

We sincerely thank all reviewers for their constructive feedback, which has substantially strengthened our manuscript. We look forward to hearing from you and are happy to make any further revisions as needed.

Sincerely,

Lin Li

Author Response File: Author Response.pdf

Reviewer 3 Report

Lin et al., 2025 submitted a review about the role of Ferroptosis in Myocardial Fibrosis. Authors summarize the current status of Ferroptosis research and give an overview about the importance of Ferroptosis in Myocardial Fibrosis. The topic is up-to-date and interesting for readers of the journal. However, more and better figures would be appropriate. Revision is recommended.

Specific points

1. Figure 1: Authors should add a figure legend better explaining the subfigures shown figure 1. Also the abbreviations must be explained in figure legend.
2. In chapter 2.2. “Lipid peroxidation” an additional figure would help readers to better understand the processes described.
3. In chapter 2.4. “Regulatory Pathways of Ferroptosis” authors should add a figure illustrating the processes described.
4. Figure 2: Authors should enlarge figure 2 to better show details. Moreover, one could use figure 2a and 2b. Authors must also add a legend explaining the figure.

 

Lin et al., 2025 submitted a review about the role of Ferroptosis in Myocardial Fibrosis. Authors summarize the current status of Ferroptosis research and give an overview about the importance of Ferroptosis in Myocardial Fibrosis. The topic is up-to-date and interesting for readers of the journal. However, more and better figures would be appropriate. Revision is recommended.

Specific points

1. Figure 1: Authors should add a figure legend better explaining the subfigures shown figure 1. Also the abbreviations must be explained in figure legend.
2. In chapter 2.2. “Lipid peroxidation” an additional figure would help readers to better understand the processes described.
3. In chapter 2.4. “Regulatory Pathways of Ferroptosis” authors should add a figure illustrating the processes described.
4. Figure 2: Authors should enlarge figure 2 to better show details. Moreover, one could use figure 2a and 2b. Authors must also add a legend explaining the figure.

 

 

Author Response

Dear Reviewer：

Thank you very much for the opportunity to revise our manuscript titled “Ferroptosis in Myocardial Fibrosis: Mechanisms and Therapeutic Insights” (Manuscript Number: antioxidants-4045664). We would also like to express our gratitude to the reviewers for their time and valuable feedback. We have carefully addressed all the comments and suggestions provided, which have greatly helped improve the quality and clarity of our work.

Please find below our point-by-point responses to the reviewers’ comments, along with the corresponding revisions made to the manuscript. We believe that these revisions have enhanced the manuscript, and we hope that the revised version meets the journal’s standards for publication.

Comment 1: Figure 1: Authors should add a figure legend better explaining the subfigures shown figure 1. Also the abbreviations must be explained in figure legend.

Response: We added a legend to Figure 1 and Figure 2, in which the legend briefly describes the content of each subplot, and added a dedicated section titled "Abbreviation" to list the full names of each abbreviation, ensuring that readers can understand the chart content without referring to the main text.

Comment 2: In chapter 2.2. “Lipid peroxidation” an additional figure would help readers to better understand the processes described.

Response: Thank you for your suggestion. Given that lipid peroxidation is the core execution mechanism of ferroptosis, we have demonstrated the process of lipid peroxidation in Figure 1b. This figure systematically presents the lipid peroxidation pathway in lipid metabolism, including the initiation, propagation, and termination stages of lipid peroxidation. The propagation stage is divided into enzymatic and non-enzymatic forms. The above content is also explained in the newly added figure legend to facilitate readers' understanding.

Comment 3: In chapter 2.4. “Regulatory Pathways of Ferroptosis” authors should add a figure illustrating the processes described.

Response: Based on the content described in this section, we have constructed a comprehensive schematic diagram of the ferroptosis regulatory network in Figure 1d, which includes the p53-Nrf2 signaling network, FSP1/CoQ10 pathway, DHODH/CoQ10 pathway, and GCH1/BH4 pathway, as well as the interaction relationships between these components. The aforementioned content is also explained in the newly added legend to facilitate readers' understanding.

Comment 4: Figure 2: Authors should enlarge figure 2 to better show details. Moreover, one could use figure 2a and 2b. Authors must also add a legend explaining the figure.

Response: We have enlarged each subplot of Figure 2 and correspondingly enlarged all fonts and symbols. Additionally, we have increased the image resolution and optimized the line thickness and contrast, significantly enhancing the clarity for both printing and screen reading. We have added legends to Figure 1 and Figure 2, with brief descriptions of the content of each subplot in the legends, and included a dedicated "Abbreviations" section to facilitate readers' understanding of the chart content.

Comment 5: The English could be improved to more clearly express the research.

Response: We have commissioned a professional medical editing company to perform native-language polishing on the full text, with a focus on optimizing sentence structure, logical coherence, and terminology accuracy. The polishing certificate has been submitted as an attachment. No substantive changes have been made to the academic content.

We sincerely thank all reviewers for their constructive feedback, which has substantially strengthened our manuscript. We look forward to hearing from you and are happy to make any further revisions as needed.

Sincerely,

Lin Li

Author Response File: Author Response.pdf

Round 2

Reviewer 2 Report

The authors have satisfactorily addressed all concerns raised in the previous review. The revisions have strengthened the manuscript, enhanced its clarity, and improved the overall rigor of the study.

I recommend the manuscript for acceptance in its current form.

The authors have satisfactorily addressed all concerns raised in the previous review. The revisions have strengthened the manuscript, enhanced its clarity, and improved the overall rigor of the study.

I recommend the manuscript for acceptance in its current form.

Reviewer 3 Report

Accept.

Accept.