PONE-D-24-25075Enhancing Lobaplatin Sensitivity in Lung Adenocarcinoma through inhibiting LDHA-Targeted Metabolic PathwaysPLOS ONE

Dear Dr. Hou,

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Academic Editor

PLOS ONE

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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: Partly

Reviewer #2: Partly

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

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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.

Reviewer #1: Yes

Reviewer #2: 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

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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: This study analyzed public databases and found that LDHA was significantly higher in tumor tissues, a conclusion that was validated in 3 pairs of tumor and adjacent tissues. Furthermore, through in vitro cell experiments, it was found that downregulation of LDHA reduced the viability of LUAD cells and increased sensitivity to LBP chemotherapy. The combination of LDHA inhibitors and oxaliplatin produced a synergistic anti-tumor effect. However, this article has several shortcomings, including but not limited to:

1. LBP is not a commonly used chemotherapy drug for lung adenocarcinoma in clinical practice, while cisplatin or carboplatin are more commonly used. Further experiments are needed to verify if similar results can be obtained with these drugs.

2. The expression of LDHA in tumor tissues in this study mainly comes from public databases, while the sample size verified by this research institution is only 3 cases, making the results unreliable.

3. The study on LDHA sensitizing LBP is limited to cell experiments and has not been validated in animal models, leading to a certain degree of uncertainty in the conclusions.

Reviewer #2: This is an interesting study on the role of Lactate pathway in the development of drug resistance in LUAD. The energy supply for cancer cells is highly dependent on the Lactose pathway and DNA repair and Nucleotide synthesis are highly energy consuming processes. Therefore it is not surprising, that LDHA inhibition enhances chemosensitivity and reduces drug resistance. The study is so far nicely conducted, but the main limitation is, that it is lacking control groups to evaluate the specific effect of LDHA inhibition on drug resistance and distinguish it from an unspecific energy depleting mechanism. For further review of this work, the introduction of control groups are mandatory.

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Reviewer #1: No

Reviewer #2: No

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Enhancing lobaplatin sensitivity in lung adenocarcinoma through inhibiting LDHA-targeted metabolic pathways

PONE-D-24-25075R1

Dear Dr. Hou,

Thank you for the efforts in revising the manuscript. While one of the reviewers still has reservations about the manuscript, the editorial team believes that the conclusions can be supported by the presented evidence. Therefore, 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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Kind regards,

Zhiming Li, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

Both reviewers have agreed that the conclusions are supported by the presented evidence in the manuscript. Therefore, while addressing reviewer #2's comments to include the control groups can further improve the validity of the conclusions, I don't think it's essential at this stage.

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

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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

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

Reviewer #1: Yes

Reviewer #2: I Don't Know

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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.

Reviewer #1: Yes

Reviewer #2: No

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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

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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 critical point concerning the control groups has unfortunately not been addessed. I rhink without those controls the conclusion outlined in the title can not been drawn from this data conclusively.

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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.

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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 #1: No

Reviewer #2: No

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