-->PONE-D-25-60628-->-->Network Pharmacological Insight into Traditional Bone Healing Practices of Sikkim, India-->-->PLOS One

Dear Dr. Deb,

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.

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Kind regards,

Sandeep Rawat, Ph.D.

Academic Editor

PLOS One

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Additional Editor Comments:

• Clarify linkage between ethnopharmacological data (FoC/RFC) and network pharmacology to avoid descriptive overlap.

• Strengthen network pharmacology with validation criteria and acknowledge predictive limitations by adding criteria for target/pathway prioritization (e.g., degree centrality, enrichment score cut-offs).

• Correct inconsistencies in informant numbers, FoC/RFC values, and botanical nomenclature in quantitative data, tables, figures, and species nomenclature.

• Improve language, reduce redundancy, and temper anecdotal efficacy claims.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

-->Comments to the Author

1. 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

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

Reviewer #1: Yes

Reviewer #2: Yes

Reviewer #3: Yes

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-->3. 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.-->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

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-->4. 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

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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 study is well-founded in Network Pharmacological Insight into Traditional Bone Healing Practices of Sikkim,

India.

Covers multiple aspects aspects and baseline data to address an immediate need to preserve and scientifically.

Comprehensive Results are lead compounds, considering biological processes, molecular functions, and cellular components involved in bone.

Reviewer #2: Network Pharmacological Insight into Traditional Bone Healing Practices of Sikkim, India, PONE-D-25-60628

Strength of the Manuscript

• An extensive cross culture ethno-pharmacological survey of an area of Sikkim Himalaya, which was less explored. This documentation work conserved valuable traditional knowledge of folklore practitioners.

• Traditional claims of folklore practitioners documented during the survey was validated using AI based network Pharmacological screening that preliminarily justified traditional claims for pharmacological uses of medicinal plants for treatment of bone fracture.

Weakness of the Manuscript

• Phytochemical inclusion criteria: From 1,043 compounds, 527 were selected after redundancy removal and ADMET screening, yet "clinical evidence" allowed retention of failures (e.g., high MW flavonoids). Specify exact ADMET parameters (Lipinski/Veber scores), violation rates, and which retained compounds link to calcium reabsorption pathways.

• Calcium reabsorption: Given that Calcium reabsorption is the critical step in bone mending, are there specific pathways anticipated in the calcium reabsorption from the network pharmacological annotations that need to addressed?

• Scientific Name of Plant: the scientific name of the all plants should be in italic.

• Languages of Manuscript: grammatical error and long sentences should me recheckfor its correctness.

Reviewer #3: Network Pharmacological Insight into Traditional Bone Healing Practices of Sikkim, India (PONE-D-25-60628)

The research is carefully executed and descriptive enough to strengthen the pharmacological knowledge of the traditionally used herbal formulation. The findings are thoughtfully integrated and offer promising therapeutic perspectives. Most importantly, such study will preserved valuable traditional healthcare knowledge of traditional healers. Moreover, all traditional healers participated in this study were included as author in this manuscript, which is very much necessary to acknowledge the credit of real knowledge holder.

However, here are some of the suggestions that can help to improve the clarity and coherence of the manuscript

• In Pathway validation for bone mending section, Eleven pathways (e.g., calcium signalling, RANKL/RANK, Vitamin D-sensitive Ca) are listed without enrichment statistics (p-values, fold-change) or hub gene metrics in the PPI network (TERT, SRC, CYP27B1). Provide quantitative enrichment data and explain how these specifically support calcium reabsorption in fracture repair.

• In Correlation of key Genes, from the top 10 genes the remarkable survival target genes AKT and STAT are common in cancer and other pathway. How does it correlate in bone mending?

• The English language is modest and contains several grammatical and typographical errors.

• Author may include detail methodology of documentation including questioners in supplementary file.

Recommended for the publication with minor correction

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Reviewer #1: Yes:Dr.Bala Krishnaiah P, ProfessorDr.Bala Krishnaiah P, ProfessorDr.Bala Krishnaiah P, ProfessorDr.Bala Krishnaiah P, Professor

Reviewer #2: Yes:Chiranjib BhattacharjeeChiranjib BhattacharjeeChiranjib BhattacharjeeChiranjib Bhattacharjee

Reviewer #3: Yes:Dr Rupesh Kumar GautamDr Rupesh Kumar GautamDr Rupesh Kumar GautamDr Rupesh Kumar Gautam

**********

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Attachments

Attachment

Submitted filename: Reviewer comments.docx

Attachment

Submitted filename: Comments Plos One.docx

-->PONE-D-25-60628R1-->-->Network Pharmacological Insight into Traditional Bone Healing Practices of Sikkim, India-->-->PLOS One

Dear Dr. Deb,

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.

==============================

ACADEMIC EDITOR:-->-->

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 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.. 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 . 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,

Sandeep Rawat, 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.

Additional Editor Comments (if provided):

• Clearly define probability cut-offs, number of compounds failing Lipinski/Veber.

• Specify whether predicted targets relate to renal Ca²⁺ or osteoblast/osteoclast intracellular Ca²⁺ signaling.

• Discussion should consistently reflect the exploratory and in silico nature of the findings.

• Several species names remain misspelled. Ensure uniform italics and correct spelling throughout text, tables, and figures.

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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: 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: 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

**********

-->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.-->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: (No Response)

Reviewer #2: the authours have carefully and satisfacrorly adressed all the queriesraised by the rtevewirs kindly accept it

Reviewer #3: The current stdy include the proper work with the authenticy. I will helpful for socity as well as researcher. Thanks a lot for the quality work.

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-->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 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 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:Dr.Bala Krishnaiah PDr.Bala Krishnaiah PDr.Bala Krishnaiah PDr.Bala Krishnaiah P

Reviewer #2: No

Reviewer #3: Yes:Dr. Rupesh K. GautamDr. Rupesh K. GautamDr. Rupesh K. GautamDr. Rupesh K. Gautam

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[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.]

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NAAS will assess whether your figures meet our technical requirements by comparing each figure against our figure specifications.

-->

Network Pharmacological Insight into Traditional Bone Healing Practices of Sikkim, India

PONE-D-25-60628R2

Dear Dr. Deb,

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.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

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If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Sandeep Rawat, Ph.D.

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments: