Title: Blood Metabolites, Mitochondrial Biofunction, and Cervical Cancer: A Bidirectional
Mendelian Randomization Study
Version: 1 Date: 20 Feb 2025
Reviewer's report:
PEER REVIEWER ASSESSMENTS:
OBJECTIVE - Full research articles: is there a clear objective that addresses one or several
testable research questions? (Brief or other article types: is there a clear objective?)
No - there are major issues
DESIGN - Is the current approach (including controls and analysis protocols) appropriate for
the objective?
No - there are major issues
EXECUTION - Are the experiments and analyses performed with sufficient technical rigor to
allow confidence in the results?
No - there are major issues
STATISTICS - Is the use of statistics in the manuscript appropriate?
No - there are issues with the statistics in the study
INTERPRETATION - Is the current interpretation/discussion of the results reasonable and not
overstated?
No - there are major issues
OVERALL MANUSCRIPT POTENTIAL - Has the author addressed your concerns sufficiently
for you to now recommend the work as a technically sound contribution? If not, can further
revisions be made to make the work technically sound?
Maybe - with major revisions
PEER REVIEWER COMMENTS:
GENERAL COMMENTS: The authors were very polite in the responses, usually agreeing with
the reviewer comments, but made a very poor effort to modify the manuscript accordingly. The
manuscript continues with serious flaws
REQUESTED REVISIONS:
My comment 1 was not included in the introduction, it should have been, as the readers must
be initially aware that many authors consider that alterations in metabolism observed in cancer
are mostly associated with tumour changes during its development, and not causation. Some
of this issue was included in some extent only in the Discussion. In Introduction, there is at
least a misleading sentence "The reprogramming of lipid metabolism in cancer cells contributes
to the initiation, progression, invasion, and metastasis of cancer[10]." As reference [10] never
refers causation. This is a very serious error, forcing erroneously support of the causation that
the authors seem so keen to justify.
My point 2 was addressed, just failing to refer how many SNPs were contained in the Finish
array. Now they included the following information "with imputation extending coverage to
rarer variants". Which imputation? Done by whom - the Finnish consortium? More information
must be provided.
My comment 3, no mention was included in the manuscript. A cautionary note should had
been included. In the response to my comment they say "This approach is consistent with
other Mendelian randomization studies, which often adopt similar thresholds (e.g., 1×10^-5
or 1×10^-6) when SNP numbers are limited." But they did not include any of this and they
did not provide any adequate reference. They also replied "Additionally, we performed several
sensitivity analyses, including the Cochran Q test and MR-Egger, to ensure the robustness of
our results." but continuing not analysing how these results replicate/support the ones obtained
by YVW. It is not enough to include supplementary tables and to say that IVW is more robust.
This is totally inadequate.
Comment 4 not addressed at all. Results continue boring. The final section added to the Results
adds nothing to the interpretation "While the IVW method identified 25 blood metabolites and
3 mitochondrial biofunctions associated with CC, it is important to highlight that additional
MR methods were also employed to validate these findings, with results provided in the
supplementary materials (Supplementary files 1–4). These supplementary analyses support the
primary results". Last sentence needs to be continued - it is only adequately missing a stop mark,
as it should not stop there.
Comment 5, an effort was done in justifying why IVW is more robust, but it is still hermetic
and not understandable by the general reader of this manuscript. Illustrative examples of their
results should had be provided. How many metabolites/mitochondria pathways are significant
in at least two of the three applied tests? Authors should have answered this simple and
obvious question. Many of the added sentences in discussion are not properly referenced, as
for example "Glutaredoxin-2 is considered one of the protective factors for CC", "Malonyl-
CoA decarboxylase (MCD) is considered one of the protective factors for CC, but interestingly,
it appears to have a dual nature." Sentence "Therefore, these two metabolites in CC may
promote tumor cell proliferation by enhancing DNA synthesis and cell cycle progression, while
also inhibiting apoptosis to some extent, thereby exerting a cancer-promoting effect." in not
supported at all in the paragraph in which it is included - it is totally wishful thinking by the
authors.
Comment 6, totally ignored. There are other data available.
ADDITIONAL REQUESTS/SUGGESTIONS:
They cannot be so assertive in the conclusions of causations, when they just mentioned before
two paragraphs of limitations of the study and the "feeling" of the large community that
metabolism is important for the progression and maybe treatment of cancer disease.