-->PONE-D-25-56812-->-->GSEA and the coexpression network approach identify novel pathway connections of molecular processes affected in Porto-sinusoidal vascular disease-->-->PLOS One

Dear Dr. Ehrhart,

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8. 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.

Additional Editor Comments (if provided):

1. Reconsider the "weak" DEG category. Use standard FDR < 0.05 (or a justified threshold) for calling DEGs. If retaining "weak" DEGs, provide a strong biological or statistical rationale for the chosen logFC cutoffs and clearly differentiate them from significant DEGs in all analyses and visualizations. Avoid including them in functional enrichment summaries unless justified).

2. : For genes without prior direct links to PSVD (e.g., GAGE12J, BARD1, RPS27A, GHRL, IL6, CD19, CDC6, TOP2A), rephrase conclusions. Focus on their statistical ranking and potential biological relevance based on known functions, but avoid labeling them as "novel" findings for PSVD without supporting evidence. Use phrases like "potential candidate", "statistically prioritized", or "suggestive of involvement".

• Ensure all figures are clear, well-labeled, and legends are unambiguous (especially Fig 2 volcano plot colors).

• Critically assess if all panels in Fig 5 are essential. Consider focusing on the core genes (5b).

• Make absolutely certain that Figs 6 and 7 effectively communicate the complex correlation and PPI structures.

3. Elaborate on the GSEA vs. WGCNA immune pathway discrepancy. Discuss the potential biological and methodological reasons.

4. Provide more nuanced biological interpretation of PPI subclusters beyond the functional labels. What specific interactions or potential regulatory roles do the hub genes play within their subclusters in the context of PSVD?

5. If feasible, briefly discuss how specific module-clinical trait correlations (beyond just diagnosis) might inform the understanding of PSVD heterogeneity or severity.

6. Sharpen the conclusion to emphasize the core finding of the immune/signaling vs. metabolic/translational/bioenergetic imbalance as the central pathogenic mechanism revealed by this integrated analysis, alongside the specific ribosomal and mitochondrial deficits. Position the "novel" genes as candidates for future validation.

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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: Yes

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

Reviewer #1: Yes

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-->3. Have the authors made all data underlying the findings in their manuscript fully available?

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Reviewer #1: Yes

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Reviewer #1: 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: In this work, the authors implemented a secondary analysis of transcriptomics data on Porto-sinusoidal vascular disease (PSVD). Specifically, the authors used both GSEA (gene set enrichment analysis) and WGCNA (weighted gene co-expression network analysis) to identify candidate modules and enriched pathways.

Major Issues:

• I don’t have any major issues with the bioinformatics approach used by the authors. With that being said, the below comments should be addressed to improve the clarity of the manuscript.

• In GSEA, looks like the authors used both significant and weakly significant (p-value > 0.05) genes. What is the rationale behind using the weak significant candidates? Did the authors try using just the significant ones?

• In the WGCNA analysis, it is not clear how many modules the authors were able to find. In Section 3.6 (Page 4, line 137), the authors specified finding 24 modules. However, in Section 4.3 (line 227), it’s mentioned that 35 distinct modules were identified. Moreover, in the Supplementary Figure (Module-trait relationship heatmap) I could find only 22 modules. This needs to be clarified.

• For constructing module PPI networks, the authors seem to have used different STRING confidence score thresholds. What is the reason/rationale for this?

• This manuscript can do with another table listing some of the top (relevant) enriched pathways (and individual genes from the DEGs/core genes) from both analyses. This can help identify robust pathways enriched in both methodologies.

Minor comments:

• Looks like the placeholder texts form the journal manuscript template are still present, like Fig 1 caption in Page 6. This needs to be fixed.

• In Section 3.3, looks like a negative sign is missing in describing the significantly weak downregulated genes. Also looks like the authors missed adding the word “weak” in this line (line 93). This should be corrected.

• Also, for the DEG categories, the authors used “significantly weak upregulated/downregulated” genes as the category names. Perhaps, using the phrase ‘significantly weak’ is confusing since the adjusted p-value thresholds used were not significant (> 0.05).

• The sentence starting in line 228 (Section 4.3) seems to be left incomplete. This needs to be fixed.

• Formatting of Figure 5 legend seems to have been messed up in the manuscript.

• In the figure legend for Figure 6, the correlation values seem to have commas instead of decimal points.

• In figure S4 (cluster dendrogram), the label on the x-axis is cut.

• Text on line 9 (Section 2) seems to have been scrambled. This needs to be fixed.

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Reviewer #1: Yes: Sudhir Ghandikota

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-->PONE-D-25-56812R1-->-->GSEA and the coexpression network approach identify novel pathway connections of molecular processes affected in Porto-sinusoidal vascular disease-->-->PLOS One

Dear Dr. Ehrhart,

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 Apr 25 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.

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 https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Cheung Kenneth Chat Pan

Academic Editor

PLOS One

Journal Requirements:

1. 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.

2. 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:

The study presents a comprehensive re-analysis of existing transcriptomics data for Porto-sinusoidal vascular disease (PSVD) using robust bioinformatics methods (GSEA and WGCNA). The findings point to a coordinated dysregulation involving immune, signaling, and metabolic pathways, which is a valuable contribution to understanding this rare disease.

1. Clarity on "Novel Pathway Connections": The title explicitly mentions "novel pathway connections," but the abstract doesn't clearly articulate what these novel connections are. While it mentions "coordinated dysregulation," it could be more explicit about the interrelationships found (e.g., the negative correlation between immune/signaling and metabolic modules).

• In the "Results and Conclusion" section, explicitly state that the study identifies novel interconnections or antagonistic relationships between these pathway clusters. For example: "This study revealed a novel coordinated dysregulation in PSVD, characterized by the simultaneous activation of immune and signaling pathways alongside the suppression of metabolic, ribosomal, and mitochondrial programs, highlighting a critical antagonistic interplay between these systems."

2. "Coordinated dysregulation" is a key finding. Can you hihglgiht at how this coordination was identified (e.g., through module eigengene correlation)? phrase like: "Through module eigengene correlation network analysis, this study revealed a coordinated dysregulation..."

3. While ribosomal proteins, ATP synthase, and serpin family members are mentioned, their significance could be further emphasized. Why are these particular molecules important?explain the consequences of their alteration. For example: "Alterations in ribosomal proteins, ATP synthase subunits, and serpin family members highlight translational, bioenergetic, and anticoagulant dysfunction, respectively, as core mechanisms."

• After introducing Hernández-Gea et al. (lines 23-26), explicitly state the gap your study fills. For example: "While Hernández-Gea et al. provided crucial insights into vascular homeostasis and oxidative phosphorylation, a comprehensive, integrated understanding of the interplay between various dysregulated biological systems in PSVD, particularly the coordinated relationships between immune, metabolic, and signaling pathways, remains elusive. Our study aims to address this by..."

• Clarify the Relationship with Hernández-Gea et al. (Lines 23-26): This is the most direct comparator study. The introduction mentions its findings (vascular homeostasis, oxidative phosphorylation, endothelial function). Briefly mention how your approach differs or goes deeper. For example, did Hernández-Gea et al. use WGCNA but not GSEA, or did they focus on different aspects of network analysis? (The discussion section does address this, but a hint in the intro would be good).

• The discussion (lines 369-372, 394-396, 402-404) highlights differences and similarities with Hernández-Gea et al. (e.g., SERPINs, APOE/APOA2, ATP synthases). Consider weaving a very high-level preview of this into the introduction to further emphasize novelty. For instance, "Building upon these findings, our integrated approach reveals a more complex, multi-systemic dysregulation, uncovering novel antagonistic relationships between immune and metabolic processes, and refining the understanding of previously implicated pathways like oxidative phosphorylation." While true, the introduction could acknowledge the hypothesized contributors to PSVD's etiology, given the mention of associated conditions (lines 17-19). This would subtly connect to the pathways explored.

• Instead of just "The mechanism of disease development for PSVD is not known" (line 15), consider: "While the precise etiology of PSVD remains unknown, its development is strongly linked to vascular alterations within the liver and is frequently associated with disorders of immunity, blood diseases, prothrombotic conditions, and drug exposure [1], suggesting a multifactorial origin involving diverse biological processes." This naturally leads into why omics are needed.

• Line 20: "Because PSVD incorporates a small, heterogeneous diseased patient group with varying physiological and histological features, there is sparse information regarding molecular pathways or processes affected in this condition." This is a slightly long sentence. Consider breaking it or rephrasing for better flow. "The small and heterogeneous nature of PSVD patient groups, coupled with varying physiological and histological features, has resulted in sparse information regarding the molecular pathways or processes affected in this condition."

Ensure consistent use of "Porto-sinusoidal vascular disease" or its abbreviation "PSVD" throughout. The current usage is generally good.

• Line 23: "Hernand´ez-Gea et al." -> "Hernández-Gea et al." (check diacritics).

• Line 28: "and next to link these genes to pathways thereby explaining the molecular mechanisms" -> "and subsequently linking these genes to pathways to explain the molecular mechanisms".

• Line 31: "are coexpressed or change" -> "are coexpressed or exhibit coordinated changes".

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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 #2: (No Response)

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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 #2: Yes

**********

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

Reviewer #2: 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.-->

Reviewer #2: Yes

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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 #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 #2: This is a well-designed and technically sound study; however, the Discussion would benefit from a focused revision to better contextualize the identified pathways within the evolving clinicopathologic understanding of porto-sinusoidal vascular disease (PSVD). In particular, the authors should more clearly link the GSEA- and coexpression network–derived pathways to established morphologic and clinical correlates of PSVD, including portal venopathy, sinusoidal remodeling, and altered hepatic microcirculation. Briefly addressing how these molecular signatures may overlap with or diverge from PSVD-like changes observed in other settings (e.g., post-transplant portal vasculopathy) would strengthen the translational relevance. The Discussion should also clarify whether the identified pathways support a primary vascular injury model, immune-mediated mechanisms, or secondary remodeling processes. Incorporation of recent clinicopathologic observations would enhance the manuscript, including: Khandakar B, Joldoshova A, Zhang X. Porto-sinusoidal vascular disease-like alterations in transplant liver biopsies: A clinicopathologic observation of transplant-associated portal vasculopathy. Hum Pathol. 2026;167:105984. doi:10.1016/j.humpath.2025.105984.

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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 #2: No

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GSEA and the coexpression network approach identify novel pathway connections of molecular processes affected in Porto-sinusoidal vascular disease

PONE-D-25-56812R2

Dear Dr. Ehrhart,

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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Kind regards,

Cheung Kenneth Chat Pan

Academic Editor

PLOS One

Additional Editor Comments (optional):

Reviewers' comments: