PCOMPBIOL-D-25-01915

Multi-Omics and Network Pharmacology Identify IGFBP1 as an m6A-Epigenetic Target of Pueraria in NSCLC Therapy

PLOS Computational Biology

Dear Dr. Qu,

Thank you for submitting your manuscript to PLOS Computational Biology. After careful consideration, we feel that it has merit but does not fully meet PLOS Computational Biology'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 within 30 days Dec 29 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 ploscompbiol@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pcompbiol/ 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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If you would like to make changes to your financial disclosure, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Eduardo Jardón-Valadez

Academic Editor

PLOS Computational Biology

Ferhat Ay

Section Editor

PLOS Computational Biology

Additional Editor Comments:

Dear Authors,

Please find below the comments and suggestions provided by the invited reviewers to assist you in preparing the revised version of your manuscript. I believe that your study is both valuable and relevant for publication in PLOS Computational Biology.

In your revision, please ensure that the aims and hypotheses are clearly stated, the figure numbering and corresponding references in the main text are consistent, and all acronyms are properly defined. Additionally, I encourage you to discuss your main findings more thoroughly, improve the logical organization of the Results section, and expand the Methods section to include details, eg, in the molecular dynamics (MD) setup, equilibration procedures, production runs, and analysis protocols.

Kind regards

Eduardo Jardon

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Please indicate by return email the full and correct funding information for your study and confirm the order in which funding contributions should appear. Please be sure to indicate whether the funders played any role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript.

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Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #1: Dear Authors

The research is informative and shows a strong computational and bioinformatics workflow (clustering, survival, mutation, CNV, immune infiltration, and pathway analysis). It reflects an advanced use of multi-omics data from TCGA and GEO.

However, the text has conceptual and methodological gaps, and the structure lacks clarity for publication in a high-impact journal.

Major Weaknesses

Lack of Clear Objective

The text jumps directly into results (m6A regulators, LUAD/LUSC analysis) without stating the central hypothesis or specific research question.

It’s unclear whether the study aims to identify prognostic markers, immune subtypes, or therapeutic targets.

Missing Methodological Details

No information on dataset size, normalization methods, statistical thresholds (e.g., adjusted p-values, FDR), or the exact bioinformatics pipeline.

The basis for clustering (consensus clustering parameters, number of clusters k, etc.) is not explained.

No Validation

There’s no mention of experimental validation (e.g., RT-qPCR, IHC, or external dataset verification).

Computational results alone may not confirm biological relevance.

Overgeneralized Conclusions

Claims about immune microenvironment regulation and clinical relevance are strong but not supported by mechanistic evidence.

No discussion of potential confounders or limitations.

Figure / Table References Missing

The text refers to results (e.g., subtypes, immune infiltration) but provides no figure or table references, which weakens reproducibility.

Weak Link to Clinical Translation

Although clinical outcomes (survival) are mentioned, there is no clear suggestion on how identified m6A regulators could be applied in diagnosis or treatment.

Language & Structure

Long, complex sentences reduce clarity.

Some transitions between LUAD and LUSC analyses are abrupt.

Recommendations

Add a clear research aim and hypothesis.

Define what biological question the study answers (e.g., “to identify m6A-based prognostic subtypes in NSCLC”).

Expand the Methods section.

Describe all data sources, preprocessing steps, and statistical thresholds.

Include package names, software versions, and cut-off criteria for DEGs or clustering.

Include experimental or external validation.

Validate expression of key m6A genes via RT-qPCR or IHC.

Use an independent GEO dataset for model verification.

Reorganize Results logically.

(a) Subtype identification →

(b) Mutation/CNV landscape →

(c) Immune infiltration →

(d) Prognostic analysis →

(e) Pathway enrichment.

Add visual evidence.

Figures showing Kaplan–Meier survival curves, heatmaps, immune scores, and m6A regulator expression patterns.

Strengthen Discussion.

Compare findings with previous studies on m6A in NSCLC.

Address limitations (e.g., reliance on public data, lack of experimental confirmation).

Improve English clarity.

Shorten sentences, avoid redundancy, and use transition phrases (“In contrast…”, “Furthermore…”).

Provide a concise conclusion.

Emphasize the novelty and practical implications (e.g., “m6A-related genes may guide immunotherapy response in NSCLC”).

Reviewer #2: This is an interesting research manuscript by Rui Li and co-workers on a topic of growing importance in the current oncotherapy landscape titled Multi-Omics and Network Pharmacology Identify IGFBP1 as an m6A-Epigenetic Target of Pueraria in NSCLC Therapy.

Overall, the strategic approach was novel in the manuscript. I am supporting the publication of this article in PLOS Computational Biology. However, before this is possible, this article will need some serious revisions.

The authors reported the Identification of targets for cancer. The dysregulation of N6-methyladenosine (m6A) modification drives progression in non-therapeutics

Few of the cases author needs to modify the author grammatical errors.

Based on the sequence anayiss, MD Simulation, Docking reviewd suggest that some merit in the paper.

This is an interesting research manuscript by Rui Li and co-workers on a topic of growing importance in the current oncotherapy landscape titled Multi-Omics and Network Pharmacology Identify IGFBP1 as an m6A-Epigenetic Target of Pueraria in NSCLC Therapy.

Originality: Excellent

Technical Quality: Good

Clarity of Presentation: Fair

Rate the overall importance of this paper to the field of Medicinal Chemistry: Top 10%

Recommended after minor revision

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes: ALI MOGHADAM

Reviewer #2: No

Figure resubmission:

Reproducibility:

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PCOMPBIOL-D-25-01915R1

Multi-Omics and Network Pharmacology Identify IGFBP1 as an m 6 A-Epigenetic Target of Pueraria in NSCLC Therapy

PLOS Computational Biology

Dear Dr. Qu,

Thank you for submitting your manuscript to PLOS Computational Biology. After careful consideration, we feel that it has merit but does not fully meet PLOS Computational Biology'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 Apr 10 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 ploscompbiol@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pcompbiol/ 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 editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'. This file does not need to include responses to formatting updates and technical items listed in the 'Journal Requirements' section below.

* 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, competing interests statement, or data availability statement, please make these updates within the submission form at the time of resubmission. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

We look forward to receiving your revised manuscript.

Kind regards,

Ferhat Ay, Ph.D

Section Editor

PLOS Computational Biology

Ferhat Ay

Section Editor

PLOS Computational Biology

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.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Authors:

Please note here if the review is uploaded as an attachment.

Reviewer #2: I have satisfied with the revision comments submitted by the Author. Even though need some minor revisions in the manuscript. I have noticed that many of the recent literatures not been cited by the authors, so I recommend to add few more important refences related to the submitted work to strengthen the quality of the manuscript.

Still manuscript needs to proof read by the English readers. So I am recommending for the minor revision.

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Have the authors made all data and (if applicable) computational code underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data and code 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 and code 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 or code —e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #2: Yes

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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 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 Privacy Policy .

Reviewer #2: Yes: SREEKANTH THOTA

Figure resubmission:

Reproducibility:

To enhance the reproducibility of your results, we recommend that authors of applicable studies deposit laboratory protocols in protocols.io, where a protocol can be assigned its own identifier (DOI) such that it can be cited independently in the future. Additionally, PLOS ONE offers an option to publish peer-reviewed clinical study protocols. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols

Dear Prof. Qu,

We are pleased to inform you that your manuscript 'Multi-Omics and Network Pharmacology Identify IGFBP1 as an m 6 A-Epigenetic Target of Pueraria in NSCLC Therapy' has been provisionally accepted for publication in PLOS Computational Biology.

Before your manuscript can be formally accepted you will need to complete some formatting changes, which you will receive in a follow up email. A member of our team will be in touch with a set of requests.

Please note that your manuscript will not be scheduled for publication until you have made the required changes, so a swift response is appreciated.

IMPORTANT: The editorial review process is now complete. PLOS will only permit corrections to spelling, formatting or significant scientific errors from this point onwards. Requests for major changes, or any which affect the scientific understanding of your work, will cause delays to the publication date of your manuscript.

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Thank you again for supporting Open Access publishing; we are looking forward to publishing your work in PLOS Computational Biology.

Best regards,

Shaun Mahony

Section Editor

PLOS Computational Biology

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