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  • Eleonora Maceroni,
  • Annamaria Cimini and
  • Massimiliano Quintiliani
  • et al.

Reviewer 1: Rocío Salceda Reviewer 2: Zhiquan Liu

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

my comments are enclosed

Comments for author File: Comments.pdf

Author Response

REVIEWER 1

This is an interesting review focus on cysteine and selenoproteins. However I have

several comments that may enhance its importance.

RESPONSE: We sincerely thank you for your thoughtful and constructive comments. We have carefully considered each of your suggestions and made the necessary revisions to improve the clarity and quality of our manuscript. Below, we provide point-by-point responses to your comments, indicating the changes made.

  1. Briefly describe the figures; in figure 1, what does TNX mean?, In figure 2,

transferrin is not mentioned in the text.                         

RESPONSE: We appreciate the Reviewer’s comments. We have added brief descriptions for each figure. In Figure 1, "TNX" was a typographical error and has been corrected to "TXN". In Figure 2 (now Figure 3), we have now included a reference to transferrin in the main text.

  1. Please introduce a figure indicating the redox reactions catalyzed by

selenoproteins.

RESPONSE: A new figure (Figure 1)  illustrating the redox reactions catalyzed by selenoproteins has been added.

  1. Show a table of selenoproteins and its distribution.

RESPONSE: We have included a table listing selenoproteins (Table 1) and their tissue distribution.

  1. Indicate the meaning of all abbreviations. SECIS, please emphasized its

biological meaning.

RESPONSE: Thank you for the comment. All abbreviations have been clarified. In particular, we have expanded the explanation of SECIS to emphasize its biological significance.

  1. In RP section, organize the genetic information in the same paragraph .

RESPONSE: Genetic information has been reorganized into a single paragraph for better coherence.

  1. There is not much information on the cysteine and selenoproteins in the diabetic

retinopathy section.

RESPONSE: We totally agree with the reviewer and we have enriched this section with additional information on the role of cysteine and selenoproteins.

  1. Line 130-131, “the retina was conducted by Hansson and Holmgren, who

analyzed the modulation of the expression of insulin-like growth factor 1 (IGF1)

during retinal development in rats. Reference?

RESPONSE: We apologize for the oversight, the missing reference for the study by Hansson and Holmgren has been included.

  1. Line 128, The thioredoxin (TXN ,TNX and GRLX are reduced, they can act by

reducing disulfide bonds ; line 150, “Their studies showed that the expression of

TNX increased in..” Line 247, “TXNIP binds to reduced TNX via a disulfide bond

…of TXN and cysteine Line 661,”  TXNIP, inhibiting it. In addition, TNXIP addition,

TNXIP  inhibits glucose…”  Please correct, should be TXN, etc.

RESPONSE: We apologize for the oversights. All instances of "TNX" have been corrected to "TXN", and "TNXIP" to "TXNIP".

  1. Line 374 ,”Furthermore, focusing on the RPE, the photoreceptors most

commonly present are cones, which not only require more..”  what does it mean?

RESPONSE: The sentence has been revised to clarify the role of cones in the RPE context.

  1. Line 405, “Several studies have shown a reduction in the redox state of GSH in

RPE cells..” please indicate the context. 

RESPONSE: We have added context regarding the reduction of GSH redox state in RPE cells.

  1. Line 427, “In the context of AMD, various mechanisms contribute to retinal

ganglion cell death, including…”, please correct, ganglion cells are not directly

affected in AMD.  

RESPONSE: The statement has been corrected to reflect that retinal ganglion cells are not directly affected in AMD.

  1. Line 472-473, “Finally, an increased sensitivity of Müller cells to osmotic stress

was observed “, out of the context for RP.

RESPONSE: The sentence has been removed to maintain relevance within the RP section

  1. “5.2. Keap1-Nrf5 pathway”, you mean Nrf2?

RESPONSE:  We apologize for the oversight, the title has been corrected to "Keap1-Nrf2 pathway".

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This review provides a concise and well-organized overview of the roles of cysteine and selenocysteine in retinal redox homeostasis. It highlights how disruptions in their metabolism contribute to oxidative stress and the progression of major retinal diseases such as AMD, RP, and DR. The authors also summarize emerging therapeutic strategies—including antioxidant supplementation, gene therapy, and redox pathway modulation—that show promise in preclinical studies. Overall, the manuscript offers valuable insights into redox-based approaches for retinal neuroprotection and sets the stage for future translational research. Given the growing interest in oxidative stress and neuroprotection in retinal research, this review is likely to attract broad attention from investigators in the field and offers a valuable foundation for future studies.

However，I have some suggestions：

  1. Why are all the words inside the boxes in Fig. 2 written in uppercase letters? It makes them difficult to understand.
  2. In Table 1, I suggest the authors provide a more detailed and separate summary—for example, categorizing by therapeutic targets, delivery methods, and treatment outcomes—to give readers a clearer understanding.
  3. The authors summarized the potential role of GPX4 in retinal degeneration and therapies targeting the RPE. Recent studies have also indicated that GPX4 has protective effects on RGCs（https://doi.org/10.1101/2025.06.03.657677）. The authors should include and discuss these studies to enrich the content.
  4. The authors have thoroughly summarized the role of oxidative stress in retinal diseases and their treatments. Based on these summaries, could the authors further discuss the advantages and limitations of these therapeutic approaches? Additionally, what recommendations do the authors have for developing more effective treatments in the future?

Author Response

REVIEWER 2:

This review provides a concise and well-organized overview of the roles of cysteine and selenocysteine in retinal redox homeostasis. It highlights how disruptions in their metabolism contribute to oxidative stress and the progression of major retinal diseases such as AMD, RP, and DR. The authors also summarize emerging therapeutic strategies—including antioxidant supplementation, gene therapy, and redox pathway modulation—that show promise in preclinical studies. Overall, the manuscript offers valuable insights into redox-based approaches for retinal neuroprotection and sets the stage for future translational research. Given the growing interest in oxidative stress and neuroprotection in retinal research, this review is likely to attract broad attention from investigators in the field and offers a valuable foundation for future studies.

RESPONSE: We sincerely thank you for your positive evaluation of our manuscript and for your insightful suggestions. We have carefully addressed each of your comments and made the corresponding revisions to enhance the clarity and depth of the review. Below are our detailed responses.

 

  1. Why are all the words inside the boxes in Fig. 2 written in uppercase letters? It makes them difficult to understand.

RESPONSE: Thank you for pointing this out. We have revised Figure 2  (now Figure 3)

to use standard capitalization, improving readability and consistency.

  1. In Table 1, I suggest the authors provide a more detailed and separate summary—for example, categorizing by therapeutic targets, delivery methods, and treatment outcomes—to give readers a clearer understanding.

RESPONSE: We have restructured Table 1 (now Table 2) to provide a more detailed and categorized summary. The table now includes separate columns for therapeutic targets, delivery methods, and treatment outcomes, offering a clearer overview for readers.

  1. The authors summarized the potential role of GPX4 in retinal degeneration and therapies targeting the RPE. Recent studies have also indicated that GPX4 has protective effects on RGCs（https://doi.org/10.1101/2025.06.03.657677）. The authors should include and discuss these studies to enrich the content.

RESPONSE: We appreciate your suggestion. We have incorporated the recent findings on the protective role of GPX4 in retinal ganglion cells, including the study you referenced (https://doi.org/10.1101/2025.06.03.657677), and discussed its implications in the context of retinal neuroprotection.

  1. The authors have thoroughly summarized the role of oxidative stress in retinal diseases and their treatments. Based on these summaries, could the authors further discuss the advantages and limitations of these therapeutic approaches? Additionally, what recommendations do the authors have for developing more effective treatments in the future?

RESPONSE: In response to your valuable comment, we have expanded the discussion section to include a critical evaluation of the advantages and limitations of current therapeutic strategies. We also offer recommendations for future research directions, including the need for targeted delivery systems, long-term safety assessments, and personalized treatment approaches.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Authors answered all my comments and  the related corrections. Just, in figure 1 TNX should be replaced by TXN

Author Response

We would like to thank again the Reviewer and we modified the Figure as suggested.

Reviewer 2 Report

Comments and Suggestions for Authors

The author has satisfactorily addressed my comments, and I have no more concerns.

Author Response

We would like to thank again the reviewer for the valuable comments.