Title: The Impact of Serum Neuregulin 4 (NRG#4) Levels on Non-Alcoholic Fatty Liver
Disease (NAFLD): A Systematic Review and Meta-Analysis
Version: 3 Date: 24 Mar 2025
Reviewer's report:
Dear editor,
Thank you for the opportunity to review your manuscript entitled "The Impact of Serum
Neuregulin 4 (NRG#4) Levels on Non-Alcoholic Fatty Liver Disease (NAFLD): A Systematic
Review and Meta-Analysis." This is a timely and important topic, and your effort in compiling
available evidence is appreciated. However, several issues need to be addressed to improve the
clarity, quality, and scientific rigor of your work.
General Comments:
The manuscript requires substantial language and grammar revision throughout. There are
numerous awkward phrasings and grammatical errors that affect the readability and clarity of
the paper.
Please update the global prevalence of NAFLD in the introduction.  The current value cited is
outdated. The most recent estimate is 30.2%, and this should be properly cited:
https://doi.org/10.1016/j.arcmed.2024.103043
Clinical Comments:
The role of Nrg4 as a clinical biomarker should be expanded upon. Discuss how it could
potentially be used for diagnosis, screening, or prognosis in real-world practice.
The authors should acknowledge the limited geographic diversity of the included studies (mainly
Asia and one from Europe), which may impact generalizability.
The phrase “Nrg4 has a protective effect” is used repeatedly. Please clarify whether this is a
correlation or causation based on the study design and findings.
The authors mention therapeutic implications briefly—this could be strengthened by discussing
how Nrg4 might be targeted in potential future treatments for NAFLD.
Statistical Comments:
The use of a fixed-effects model is inappropriate given the high heterogeneity (I² = 98.5%). A
random-effects model should be used, or the choice should be strongly justified.
Although meta-regression was performed, none of the findings were statistically significant (all
p > 0.05). These results should be presented as exploratory or hypothesis-generating.
The funnel plot and Egger’s test are mentioned, but the actual plots and p-values are missing.
Please include these in the results or as supplementary material.
The subgroup analysis by Nrg4 cutoff is helpful, but the rationale for selecting a 4 ng/ml cutoff
should be explained more clearly, supported by references or prior studies.
Title: The Impact of Serum Neuregulin 4 (NRG#4) Levels on Non-Alcoholic Fatty Liver
Disease (NAFLD): A Systematic Review and Meta-Analysis
Version: 3 Date: 24 Mar 2025
Reviewer's report:
Dear editor,
Thank you for the opportunity to review your manuscript entitled "The Impact of Serum
Neuregulin 4 (NRG#4) Levels on Non-Alcoholic Fatty Liver Disease (NAFLD): A Systematic
Review and Meta-Analysis." This is a timely and important topic, and your effort in compiling
available evidence is appreciated. However, several issues need to be addressed to improve the
clarity, quality, and scientific rigor of your work.
General Comments:
The manuscript requires substantial language and grammar revision throughout. There are
numerous awkward phrasings and grammatical errors that affect the readability and clarity of
the paper.
Please update the global prevalence of NAFLD in the introduction.  The current value cited is
outdated. The most recent estimate is 30.2%, and this should be properly cited:
https://doi.org/10.1016/j.arcmed.2024.103043
Clinical Comments:
The role of Nrg4 as a clinical biomarker should be expanded upon. Discuss how it could
potentially be used for diagnosis, screening, or prognosis in real-world practice.
The authors should acknowledge the limited geographic diversity of the included studies (mainly
Asia and one from Europe), which may impact generalizability.
The phrase “Nrg4 has a protective effect” is used repeatedly. Please clarify whether this is a
correlation or causation based on the study design and findings.
The authors mention therapeutic implications briefly—this could be strengthened by discussing
how Nrg4 might be targeted in potential future treatments for NAFLD.
Statistical Comments:
The use of a fixed-effects model is inappropriate given the high heterogeneity (I² = 98.5%). A
random-effects model should be used, or the choice should be strongly justified.
Although meta-regression was performed, none of the findings were statistically significant (all
p > 0.05). These results should be presented as exploratory or hypothesis-generating.
The funnel plot and Egger’s test are mentioned, but the actual plots and p-values are missing.
Please include these in the results or as supplementary material.
The subgroup analysis by Nrg4 cutoff is helpful, but the rationale for selecting a 4 ng/ml cutoff
should be explained more clearly, supported by references or prior studies.
Please review this paper.
user
Title: The Impact of Serum Neuregulin 4 (NRG#4) Levels on Non-Alcoholic Fatty Liver
Disease (NAFLD): A Systematic Review and Meta-Analysis
Version: 3 Date: 24 Mar 2025
Reviewer's report:
Dear editor,
Thank you for the opportunity to review your manuscript entitled "The Impact of Serum
Neuregulin 4 (NRG#4) Levels on Non-Alcoholic Fatty Liver Disease (NAFLD): A Systematic
Review and Meta-Analysis." This is a timely and important topic, and your effort in compiling
available evidence is appreciated. However, several issues need to be addressed to improve the
clarity, quality, and scientific rigor of your work.
General Comments:
The manuscript requires substantial language and grammar revision throughout. There are
numerous awkward phrasings and grammatical errors that affect the readability and clarity of
the paper.
Please update the global prevalence of NAFLD in the introduction.  The current value cited is
outdated. The most recent estimate is 30.2%, and this should be properly cited:
https://doi.org/10.1016/j.arcmed.2024.103043
Clinical Comments:
The role of Nrg4 as a clinical biomarker should be expanded upon. Discuss how it could
potentially be used for diagnosis, screening, or prognosis in real-world practice.
The authors should acknowledge the limited geographic diversity of the included studies (mainly
Asia and one from Europe), which may impact generalizability.
The phrase “Nrg4 has a protective effect” is used repeatedly. Please clarify whether this is a
correlation or causation based on the study design and findings.
The authors mention therapeutic implications briefly—this could be strengthened by discussing
how Nrg4 might be targeted in potential future treatments for NAFLD.
Statistical Comments:
The use of a fixed-effects model is inappropriate given the high heterogeneity (I² = 98.5%). A
random-effects model should be used, or the choice should be strongly justified.
Although meta-regression was performed, none of the findings were statistically significant (all
p > 0.05). These results should be presented as exploratory or hypothesis-generating.
The funnel plot and Egger’s test are mentioned, but the actual plots and p-values are missing.
Please include these in the results or as supplementary material.
The subgroup analysis by Nrg4 cutoff is helpful, but the rationale for selecting a 4 ng/ml cutoff
should be explained more clearly, supported by references or prior studies.
assistant