-->PONE-D-25-04384-->-->The Ketogenic Diet Alleviates Autoimmune Thyroiditis Caused by Th17/Treg Imbalance by Inhibiting the HMGB1/NLRP3 Signaling Pathway-->-->PLOS ONE

Dear Dr. Gao,

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[This work was supported by General Program of the National Natural Science Foundation of China (82274455); Youth Program of the National Natural Science Foundation of China (82104805); Key Research Project of the Liaoning Provincial Department of Education (JYTZD2023196, JYTMS20231828); Joint Fund of the Liaoning Provincial Science and Technology Department (2023-MSLH-154, 2023-MSLH-147); Yin Yuanping National Famous Traditional Chinese Medicine Expert Inheritance Studio (202205); Reserve Project of Basic Scientific Research in Liaoning Colleges and Universities (2024-YJTCB-045).].

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-->Comments to the Author

1. Is the manuscript technically sound, and do the data support the conclusions?

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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-->2. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: No

Reviewer #3: Yes

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The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: No

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Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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-->5. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: The manuscript Yue Luo et al. investigates the evaluation the therapeutic efficacy of a ketogenic diet in ameliorating sodium iodide-induced experimental autouimmune thyroiditis in murine models. Given that this study is able to conclude that the potential of ketogenetic diet to improve the autoimmune response, the results of this study will certainly be of interest for readers of Plos One.

The manuscript is generally well written, current issues are around clarification, provision of further explanations in some places requested.

Generally, there should be comments included on inflammatory values (and other analyses results) and whether they are in a low-medium-or high range.

Actually, in L3 one meta-analysis is mentioned - is there only one? IF not, why was this one selected?

Write the reference for this sentence In recent years, the incidence of AIT has been increasing year by year, and its etiology is related to genetic susceptibility, environment, diet, infection, and other factors (L5).

Figure 5.A. is difficult to see unless blow up. I feel it may be better to concentrate on the primary outcome measures.

Some other specific issues; add references in the method session.

Explain in below tables and figures, the statistical analysis used for the data.

Add more reference in meta analysis and systematic review, so the discussion would be deep interpretation and logical analysis of research results.

Reviewer #2: Summary

The summary should be shortened to present the main conclusions more concisely.

Introduction

The hypothesis is well stated, and the introduction section is appropriately structured.

Materials and Methods:

“NOD.H-2 h4 mice were selected as the ideal animal model for AIT. The mice were provided with free access to 0.05% sodium iodide water and were developed into an AIT animal model after 8 weeks.”

Was this distilled or ionized water? Was it confirmed whether the iodine intake was at the intended level?

“control group (ZC), normal diet (ND) and ketogenic diet group (KD)”

The specific diet compositions for these groups are not described. Additionally, the group names ZC and ND are too similar, which may lead to misinterpretation.

“A total of 60 NOD.H-2h4 mice at 8 weeks of age”…

What were their body weights?

Was a reference used when formulating the ketogenic diet?

“with no gender restriction”

This statement is inappropriate. Sex differences may influence susceptibility to metabolic conditions and thus affect the outcomes.

“a standard diet”

The nutritional composition of the diets should be presented, e.g., in a table similar to Table 1.

“If the data did not meet the criteria for normal distribution or equal variance, non-parametric tests were employed, with appropriate corrections for multiple comparisons”

The specific statistical tests used should be clearly stated.

Results, Discussion, and Conclusion:

These sections are well-structured.

Tables:

8. “The feed formulations”

Only one diet is provided. The diets of the “normal control group (ZC), normal diet (ND), and ketogenic diet group (KD)” are not defined. The nutrient compositions should be included.

What does “normol” mean?

Figures:

10. Although sodium iodide was administered for 8 weeks, the figure gives the impression that it was discontinued afterward. Is this correct? What was the rationale behind this implementation? The manuscript does not explain the reason for this interruption, and it should be clarified.

Reviewer #3: Abstract:

This study investigates the effects of the ketogenic diet on antioxidant capacity, immune response, and inflammation in a sodium iodide-induced autoimmune thyroiditis (AIT) mouse model. The aim of the study is to observe the anti-AIT effects of the ketogenic diet in iodine-induced NOD.H-2h4 mice and provide a theoretical basis for understanding the mechanism of the ketogenic diet in AIT treatment, particularly explained through the HMGB1/NLRP3/Caspase-1 signaling pathways.

Introduction:

The introduction provides an overview of the research topic, information on autoimmune thyroiditis (AIT), the mouse model used, and the potential benefits of the ketogenic diet in autoimmune diseases. The primary objective of the study is to examine the effects of the ketogenic diet on AIT in mice and understand its mechanisms, particularly through the HMGB1/NLRP3/Caspase-1 pathways. However, further detailed explanations of the autoimmune and pro-inflammatory markers used (e.g., TPOAb, TGAb, TNF-α, IL-6, IL-18) would help the reader better understand the significance of these markers and the study's focus.

Methods:

The methods section is well-structured, and the parameters and methods used are explained in detail. The investigation of autoimmune markers (TPOAb, TGAb) and pro-inflammatory cytokines (TNF-α, IL-6, IL-18) is critical for understanding immune response and inflammation. However, further clarification of the reasons for selecting these markers and how they are related to the effects of the ketogenic diet on AIT would improve the comprehensibility of the study. Additionally, providing more information about the experimental timeline and the dose-response relationship between sodium iodide and the ketogenic diet would enhance the reproducibility of the study.

Results:

The results are presented clearly, demonstrating that the ketogenic diet alleviated autoimmune thyroiditis induced by high iodine intake in mice. Specifically, the ketogenic diet was found to reduce inflammatory markers, decrease oxidative stress, and increase antioxidant levels. Moreover, the ketogenic diet reduced the expression of the NLRP3/ASC/Caspase-1 signaling pathway and corrected the Th17/Treg imbalance. These findings provide valuable insights into the potential effects of the ketogenic diet. However, reporting the statistical results and p-values not only under the figures but also within the text could further support the findings.

Discussion:

The discussion section links the study's findings to the existing literature, elucidating the potential mechanisms of the ketogenic diet's effects on AIT. The effects of the ketogenic diet on inflammatory cytokines, oxidative stress, and immune modulation are well explained. However, a deeper exploration of the modulation of the HMGB1/NLRP3/Caspase-1 pathways could provide more detailed information on how these pathways operate. Additionally, comparing the ketogenic diet with other autoimmune diseases or dietary interventions could help contextualize the findings in a broader scope. Discussing the potential clinical implications of these findings would also enhance the study's overall relevance.

Conclusion:

The conclusion effectively summarizes the key findings, emphasizing that the ketogenic diet alleviated autoimmune thyroiditis and restored immune balance. The study's limitations were acknowledged, and suggestions for future research were provided. Both the discussion and conclusion sections present the findings and their possible implications effectively.

Suggestions for Improvement:

1. Clarification of Markers: In the introduction, including a brief explanation of the autoimmune and pro-inflammatory markers (e.g., TPOAb, TGAb, TNF-α) would be beneficial for readers who may not be familiar with the subject.

2. Statistical Transparency: Including p-values or confidence intervals for the results in the results section would support the findings and provide readers with more insight into the reliability and significance of the data.

3. Mechanistic Review: The discussion section could be strengthened by a more in-depth examination of the effects of the ketogenic diet on the HMGB1/NLRP3/Caspase-1 signaling pathways. More information on how these pathways are modulated and their relationship with other autoimmune diseases or dietary interventions could be added.

4. Clinical Applications: Including a brief section on the clinical applications of the study, especially discussing the potential effects on human autoimmune diseases, would help the study appeal to a broader audience.

5. Limitations and Future Research: While the study's limitations were addressed, discussing potential confounding factors (e.g., differences in mouse strain, variations in diet composition) and recommending specific areas for future research would be important to expand the scope of the study.

**********

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Reviewer #1: Yes: Ratih Wirapuspita WisnuwardaniRatih Wirapuspita Wisnuwardani

Reviewer #2: No

Reviewer #3: No

**********

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<div>PONE-D-25-04384R1-->-->The Ketogenic Diet Alleviates Autoimmune Thyroiditis Caused by Th17/Treg Imbalance by Inhibiting the HMGB1/NLRP3 Signaling Pathway-->-->PLOS ONE

Dear Dr. Yang,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

Please submit your revised manuscript by Oct 19 2025 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

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• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols..

We look forward to receiving your revised manuscript.

Kind regards,

Mehran Rahimlou, PhD

Academic Editor

PLOS ONE

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If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

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Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #1: (No Response)

Reviewer #2: All comments have been addressed

Reviewer #3: All comments have been addressed

**********

-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Partly

Reviewer #2: Yes

Reviewer #3: Yes

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

-->4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

-->5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.-->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

-->6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)-->

Reviewer #1: Yue Luo et al. wrote an article aiming to investigate the therapeutic potential of a ketogenic diet in ameliorating iodine-induced autoimmune thyroiditis in mice, focusing on its effects on inflammation, oxidative stress, immune pathways, and thyroid autoimmunity. I believe this article may be of interest to the PLOS ONE, but several aspects still require improvement to strengthen its scientific contribution. Yue Luo et al. wrote an article aiming to investigate the therapeutic potential of a ketogenic diet in ameliorating iodine-induced autoimmune thyroiditis in mice, focusing on its effects on inflammation, oxidative stress, immune pathways, and thyroid autoimmunity. I believe this article may be of interest to the PLOS ONE, but several aspects still require improvement to strengthen its scientific contribution.

First, the explanation of the research aims needs to be clarified. Furthermore, the description of ketogenic diet requires more detail. In particular, the article should explain how ketogenetic diet, inflammation, oxidative stress, immune pathways, and thyroid autoimmunity were treated during the experience. This is important to ensure the validity and reproducibility of the variables estimates.

Second, the method used has the weakness. Please explain it in the discussion section, as ELISA Kit has the limitation. In addition, the limitations of using ELISA Kit to assess IL should be acknowledged in more depth. Specifically, the potential measurement bias associated with other measurements, should be discussed both in the discussion and limitations sections.

ABSTRACT

Please consider revising the RESULTS section of the abstract to keep it concise, and clear

Tables 1 and 2 have been revised for better clarity and are now left-aligned, formatted according to the journal guidelines

Reviewer #2: "There is an error in Table 1, the normal diet is unclear. The group names in the figures remain the same as before." "There is an error in Table 1, the normal diet is unclear. The group names in the figures remain the same as before."

Reviewer #3: (No Response)(No Response)

**********

-->7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our For information about this choice, including consent withdrawal, please see our Privacy Policy..-->

Reviewer #1: Yes: Ratih Wirapuspita WisnuwardaniRatih Wirapuspita Wisnuwardani

Reviewer #2: No

Reviewer #3: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at . PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.. Please note that Supporting Information files do not need this step.

-->PONE-D-25-04384R2-->-->The Ketogenic Diet Alleviates Autoimmune Thyroiditis Caused by Th17/Treg Imbalance by Inhibiting the HMGB1/NLRP3 Signaling Pathway-->-->PLOS One

Dear Dr. Yang,

Thank you for submitting your revised manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised by the reviewer.

Please submit your revised manuscript by Feb 16 2026 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:-->

• A letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.
• A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.
• An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

-->If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at . Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols..

We look forward to receiving your revised manuscript.

Kind regards,

Kota V Ramana, Ph.D.

Academic Editor

PLOS One

Journal Requirements:

If the reviewer comments include a recommendation to cite specific previously published works, please review and evaluate these publications to determine whether they are relevant and should be cited. There is no requirement to cite these works unless the editor has indicated otherwise.

Please review your reference list to ensure that it is complete and correct. If you have cited papers that have been retracted, please include the rationale for doing so in the manuscript text, or remove these references and replace them with relevant current references. Any changes to the reference list should be mentioned in the rebuttal letter that accompanies your revised manuscript. If you need to cite a retracted article, indicate the article’s retracted status in the References list and also include a citation and full reference for the retraction notice.

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Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.-->

Reviewer #1: All comments have been addressed

Reviewer #2: All comments have been addressed

Reviewer #3: (No Response)

**********

-->2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented. -->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

-->3. Has the statistical analysis been performed appropriately and rigorously? -->

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

**********

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Reviewer #2: Yes

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Reviewer #1: This paper, authored by Xiao Yang et al., investigates the therapeutic potential of a ketogenic diet (KD) in a murine model of iodine-induced Autoimmune Thyroiditis (AIT). This topic is highly relevant to the scope of PLOS ONE due to its translational focus on diet modification for managing autoimmune disorders.

Abstract

Mention the data analysis used. What was the percentage increase in TgAb/TPOAb levels, enhanced thyroid lymphocytic infiltration, elevated proinflammatory cytokines, and aggravated oxidative stress? What was the p-value for the difference?

Methods

How many mice were used?

Discussion

Add a section at the end of the session for the strengths and weaknesses of the research.

Reviewer #2: (No Response)

Reviewer #3: Based on the reviewer's comments, I see that the necessary corrections have been made appropriately. I did not encounter any errors in spelling, punctuation, or other grammatical rules during my evaluation

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Reviewer #1: Yes: Ratih Wirapuspita WisnuwardaniRatih Wirapuspita Wisnuwardani

Reviewer #2: No

Reviewer #3: No

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The Ketogenic Diet Alleviates Autoimmune Thyroiditis Caused by Th17/Treg Imbalance by Inhibiting the HMGB1/NLRP3 Signaling Pathway

PONE-D-25-04384R3

Dear Dr. Yang,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

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Academic Editor

PLOS One

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