Decoding the CD36-Centric Axis in Gastric Cancer: Insights into Lipid Metabolism, Obesity, and Hypercholesterolemia

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript provides a systematic exploration of CD36 as a molecular intersection linking obesity, hypercholesterolemia, and gastric cancer. It employs multi- database integration, pathway enrichment analysis, and clinical sample correlations. The topic is timely, well-structured, and potentially significant for translational medicine.

However, there are several issues that need to be addressed before the manuscript can be accepted.

Issue1 : The manuscript contains only six figures, some of which present relatively basic data (e.g., Venn diagrams, Kaplan–Meier curves). For a review-style article, the figure count and informational density are insufficient.

Suggestion: Consider adding the following types of visual content:

A comprehensive diagram of the CD36 regulatory network.

A consolidated figure illustrating the intersection of lipid metabolism, inflammation, and EMT.

A schematic of the multi-database integration workflow.

Visuals showing CD36 expression across gastric cancer molecular subtypes.

Issue2 : While CD36 is indeed a key intersecting gene, the manuscript attributes nearly all mechanistic insights to it, potentially neglecting other important regulators.

Suggestion: Present a more balanced view by discussing the roles of other relevant genes in lipid metabolism and tumor progression, showing how they interact with or parallel CD36’s function.

Issue3: The mechanisms proposed for CD36 (involving PPAR-γ, NF-κB, PI3K/AKT, etc.) are largely inferred from literature and in silico analyses, without experimental validation.

Suggestion:

Provide a detailed mechanistic illustration.

If available, include experimental data (e.g., from cell or animal models).

Otherwise, clearly distinguish between "predicted" and "experimentally confirmed" mechanisms in the discussion.

Issue4 : Although CD36 is linked to prognosis and staging, the manuscript lacks a thorough discussion of its clinical applicability (e.g., diagnostics, therapeutic targeting).

Suggestion:

Discuss potential therapeutic interventions, including CD36 antagonists or inhibitors of downstream pathways.

Address whether CD36 can serve as a non-invasive biomarker (e.g., in blood).

Highlight how CD36 expression might predict responses to immunotherapy or metabolic drugs.

Issue5 : The study relies heavily on TCGA data, which lacks detailed clinical variables such as BMI, lipid profiles, or H. pylori infection status, limiting the strength of the obesity or hypercholesterolemia correlations.

Suggestion:

Expand the “Limitations” section to discuss this in more depth.

Suggest validation using metabolic cohort data or prospective clinical studies.

Issue6. Please carefully review the cited references. It appears that the authors did not thoroughly check them before submission.

Author Response

Please see the attachment

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript is well written and clear. 

All the sections are well conceived, the results achieved interesting and potentially meaningful for clinical implications.

Few minor points:

1) the authors are suggested to enrich the introduction by adding more data about gastric cancer clinical management and therapy options;

2) a comment should be provided about the results of this study and both systemic inflammation in gastric cancer

3) brief mention to angiogenesis-related miRNA in gastric cancer should be added together with the following reference Giuppi M, La Salvia A, Evangelista J, Ghidini M. The Role and Expression of Angiogenesis-Related miRNAs in Gastric Cancer. Biology (Basel). 2021 Feb 12;10(2):146. doi: 10.3390/biology10020146. PMID: 33673057; PMCID: PMC7918665. 

Author Response

Please see the attachment.

Author Response File: Author Response.docx