PONE-D-24-43295Uncovering Common Disease Mechanisms and Critical Biomarkers in Crohn's Disease with Concurrent Psoriasis and Exploring Potential Therapeutic AgentsPLOS ONE

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Reviewer #1: Yes

Reviewer #2: Partly

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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5. Review Comments to the Author

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Reviewer #1: In this article, Liu et al reported the important molecules and mechanisms responsible for the concomitance of Crohn's disease and Psoriasis by using quantitative bioinformatics utilizing a publicly available RNA sequencing repository. They found that among the identified common DEGs, 40 genes were downregulated and 37 were upregulated, totaling 77 genes. Crohn's disease and Psoriasis had a higher concentration of pathways associated with inflammation. After validation, functionality of hub genes was confirmed for S100A12, CXCL8, IL1RN, S100A9, CXCL10, MMP1, CXCL1, FPR1, CXCR2, and S100A8. The hub genes showed an increase in expression in response to neutrophil infiltration. The expression of S100A12, CXCL8, IL1RN, S100A9, CXCL10, MMP1, CXCL1, FPR1, CXCR2, and S100A8 was found to be significantly linked to immune processes such as neutrophil activation, neutrophil chemotaxis, and neutrophil migration associated with Crohn's and Psoriasis disease. They concluded that S100A12, CXCL8, IL1RN, S100A9, CXCL10, MMP1, CXCL1, FPR1, CXCR2, and S100A8 as the central genes in the pathogenesis of CD and Psoriasis comorbidity. The significance of neutrophil infiltration in promoting inflammatory and immune-mediated dysfunction seems to be crucial in the etiology of concurrent Crohn's and Psoriasis, offering an avenue for diagnostic and therapeutic methods. These are very interesting research results. The research method used is appropriate, using an exclusive analysis method. The results obtained are reasonable and very interesting. The discussion items are also very interesting data and discussions, although the contents of the discussions are very diverse due to the exclusive analysis. There are no particularly inappropriate parts or additional questions.

Reviewer #2: In the manuscript, the authors reported that Crohn’s disease and psoriasis share significant inflammatory pathways, yet the molecular mechanisms underlying their co-occurrence remain unclear. Using publicly available RNA sequencing data from the Gene Expression Omnibus, the study employed bioinformatics approaches to identify differentially expressed genes (DEGs) and protein-protein interaction (PPI) networks associated with both diseases. The analysis revealed 77 common DEGs, with 40 downregulated and 37 upregulated genes, highlighting key inflammatory pathways. Validation confirmed the central role of hub genes, including S100A12, CXCL8, IL1RN, S100A9, CXCL10, MMP1, CXCL1, FPR1, CXCR2, and S100A8, which were strongly linked to neutrophil activation, chemotaxis, and migration. These findings may imply that neutrophil infiltration plays a pivotal role in the shared pathogenesis of Crohn’s disease and psoriasis, offering potential diagnostic and therapeutic targets. To enhance the manuscript, the following issues need to be addressed appropriately.

Major Comments

• It is unclear whether the psoriasis dataset includes patients with concurrent Crohn’s disease and vice versa. If multiple patients in each dataset have both diseases, this could introduce bias in the hub gene analysis results. Clarification on this point is necessary.

• To enhance clinical validation, the expression levels of the identified hub genes should be confirmed in patients who have both Crohn’s disease and psoriasis.

• While the study mentions a 9.6% prevalence of psoriasis in Crohn’s disease, there is no discussion on the prevalence of Crohn’s disease among psoriasis patients. A bidirectional approach is essential when examining the relationship between these two diseases. Additional discussion in the Introduction and Discussion sections is recommended.

• Psoriasis comprises multiple subtypes, including psoriasis vulgaris, psoriatic arthritis, and pustular psoriasis, each associated with distinct genetic polymorphisms. It is important to clarify which specific subtype(s) are represented in the psoriasis dataset and whether a similar classification exists for Crohn’s disease in the dataset used.

• The identified hub genes are primarily associated with general immune and inflammatory responses. However, there is insufficient discussion on why these specific genes are particularly relevant in the comorbidity of Crohn’s disease and psoriasis. A deeper mechanistic analysis and discussion would strengthen the novelty of the findings.

Minor Comment

• In the Abstract, the abbreviation PPI (Protein-Protein Interaction) appears for the first time without explanation. A brief description should be provided to ensure clarity for readers.

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Reviewer #1: No

Reviewer #2: No

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Uncovering Common Disease Mechanisms and Critical Biomarkers in Crohn's Disease with Concurrent Psoriasis and Exploring Potential Therapeutic Agents

PONE-D-24-43295R1

Dear Dr. Wang,

We’re pleased to inform you that your manuscript has been now 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,

Laura Calabrese

Academic Editor

PLOS ONE