Review for 10.1186/s12876-025-03898-9 (2025)

Title: Unveiling gastric precancerous stages: metabolomic insights for early detection and
intervention
Version: 3 Date: 02 Mar 2025
Reviewer:  Anwar Ashraf Abouelnasr
Reviewer's report:
Dear Authors, please address the following points below
-The study includes a total of 98 patients for metabolomic analysis, but the overall sample size
might be considered small, especially when considering the diversity of gastric lesions and
potential confounding factors. A larger sample size could increase the statistical power of the
study, particularly when identifying minor but significant differences between AG, IM, and
normal tissues.
-The study uses cross-sectional data from patients at different stages of GC progression, but it
lacks longitudinal data to track how metabolic changes evolve. Including a longitudinal design
would provide more insight into the temporal progression of metabolic alterations from normal
gastric tissue to AG, IM, and eventually invasive GC, helping to identify early biomarkers of
progression.
-While the manuscript provides a comprehensive analysis of tissue samples, there is little
exploration of how these findings relate to peripheral biomarkers (such as blood or urine), which
would be more easily accessible in clinical settings. It would be helpful to investigate whether
the identified metabolic alterations in tissue samples are reflected in peripheral fluids, improving
the potential for non-invasive diagnostic tests.
-There is limited information on how other factors (e.g., Helicobacter pylori infection, diet,
or medication use) might have impacted the metabolic profiles observed. The absence of data
or controls for these confounding variables could introduce bias in the interpretation of the
metabolic alterations observed in AG and IM tissues.
-Although the results are promising, the manuscript does not provide enough insight into how
these findings might translate to practical clinical applications. Further discussion on how these
metabolomic biomarkers could be integrated into routine clinical practice for early detection
and risk stratification would strengthen the potential impact of the study.
-While the study identifies key metabolites and their potential for distinguishing between
different gastric tissue stages, the manuscript lacks an in-depth discussion of the underlying
biochemical or molecular mechanisms driving the observed metabolic alterations. For example,
while sphingosine’s role in inflammation and carcinogenesis is mentioned, further explanation
of how these metabolic changes contribute to the progression from normal tissue to IM or AG
would enhance the manuscript's impact. More detailed mechanistic insights into why and how
these metabolites are altered could strengthen the paper.
-The cell-level validation is valuable, but the manuscript mentions that only
glycerophosphocholine, malate, and tiglylcarnitine were assessed for cell viability under the
MNNG treatment. Further validation, especially for sphingosine and #-glutamylglutamic acid,
would have strengthened the conclusions. Additionally, examining the functional roles of these
metabolites in more diverse cellular contexts (e.g., in gastric cancer cell lines or animal models)
would further substantiate the relevance of these biomarkers to the disease process.
-The discussion does not address potential confounding factors, such as patient lifestyle, diet, or
the presence of Helicobacter pylori infection, which may also impact metabolic profiles. These
factors could influence the findings and should be accounted for or at least discussed as potential
limitations of the study.