The Pathophysiological Interrelationship Between Metabolic Dysfunction-Associated Steatotic Liver Disease and Cardiovascular Disease

Round 1

Reviewer 1 Report

The review from Gal and collaborators covers an interesting and hot topic, namely the relationship between MASLD and CVD. However, I have several concerns about the structure and the organization of the manuscript, that must be ameliorated before considering it for publication. 

My main issue is that the review is too narrative and lacks a deep mechanistic evaluation of the links between MASLD and CVD, mainly regarding the molecular mechanisms. I would recommend focusing on one aspect (for example, considering the focus of the journal, the role of oxidative stress in MASLD/CVD) and deepen the molecular mechanisms regulating this. 

The English language should be carefully revised. 

Please revise the language, there are many typos throughout the text.

Please insert more mechanistic detail in the figure regarding MASLD pathogenesis, and add at least another figure linking the mechanism of MASLD with CVD.

Please carefully revise the paragraph regarding the biomarkers, adding more information on their relevance/possible validation with supporting data, specifying if they have been obtained in animal models or humans.

Please revise the all text, eliminating redundancy and focusing on oxidative-stress related mechanisms. 

Please focus on timely and relevant references.

 

 

Author Response

Dear Reviewer 1,

Thank you for the opportunity to revise our manuscript "The pathophysiological interrelationship between metabolic-dysfunction associated steatosis liver disease and cardiovascular diseases" (Manuscript ID: antioxidants-4223391).

We are grateful to the reviewers for the constructive feedback. We have addressed every comment below and believe the revised manuscript is substantially stronger as a result.

Comment nr. 1 The topic is extremely interesting and up-to-date. However, this review is a descriptive list of observations, without an attempt to an organic interpretation.

Answer to comment nr. 1: We would like to thank the reviewer comment. We are fully aware of this topic importance, and with this resubmitted version we tried to comply with the helpful and positive feed-back given us by the reviewers. To answer to your comment, in this re-edited version we restructurised the entire paper, we even added the requested interpretation by adding a subtopic, which summarises the conclusions and the important relevance of all research result, which can be a helpful knowledge in everyday medical activity. Our research group focuses on a novel bioimpedance spectral analysis based device, which can detect the early stages of MASLD. Our goal is to extend our research to detect the early appearance of the CVD. In our paper we emphasized the crosstalks between liver-heart. To have a clinical impact our desire is to be able to detect the early disease development, so clinicians can implement a timely therapeutical strategy.  

Comment nr. 2 This review lacks of a real conclusion. The authors should at least try to integrate all the mechanistic/descriptive data they listed to provide a crithical interpretation of the topic.

Answer to comment nr. 2. To provide a better interpretation of the topic we added a new subchapter which focuses on the therapeutic approach of this multiorgan-related disease. We are aware, the vastness of the topic, but this added new chapter highlights the numerous clinical trials that have been conducted and some of the results are implemented giving clinicians a better toolkit to provide a succesfull healthcare service.

Comment nr. 3.The review is very long, some concepts are repeated without the construction of a structured scenario.

Answer to comment nr. 3. We tried to edit a more concise, focused and accurate presentation. We have restructurised the original paper thus we eliminated redundant parts.

Comment nr. 4. The reference list is extremely long, some of them are redundant (it's not an auto-citation issue)

Answer to comment nr. 4 Some of the references were cut out, but we tried to maintain a balanced approach, by providing the original paper and other articles, which were published afterwards. We tried to validate our statesments by giving a neutral approach, and focusing only the relevant referance on the presented topic. The topic vastness made us aware that this issue presented by our research group is extremely long, so the reference list mirrors the topics interests among researchers.

Comment nr. 5. The authors should include at least other 2 mechanistic figures. The one which is present in the main text offers a general picture of the topic, and lacks of mechanistic details

Answer to comment nr. 5 We are grateful for this useful comment! We provided two extra figures. One added chart focuses on the importance of the antioxidants (glutathione). The second figure was inserted by simplifing the intrahepatic molecular pathways.

Comment nr. 6. As stated before, the review is mainly narrative. It is a comprehensive summary of what is present in the current literature, but some paragraph are redundant and there is a general lack of interpretation.

Answer to comment nr 6. The review was originally written in a narrative manner. Since the provided informations were written to address a wider audience. The enlisted findings and statements were addressed to researchers and clinicians as well. To ensure the wider impact of the re-submitted article we tried to eliminent redundant paragraphs. At the end of the article we summarised the main conclusion and further research goals. We would like to thank you again for the appreciative comments! We revised our paper according to the comments given to us, and we tried to improve the language as well.

Hope the revised paper will be published.

Best regards,

corresponding authors: Dr. Gál, Dr. Tóth

Reviewer 2 Report

 

1. The review addresses a relevant topic, but the review type and methodology are insufficiently defined. The authors should clearly state that this is a narrative review and provide minimal methodological transparency regarding literature search and selection.
2. The manuscript is predominantly descriptive and requires stronger critical synthesis. Mechanisms are extensively listed, but the evidence is not sufficiently prioritized according to robustness and clinical relevance.
3. Redundancy is substantial. Several concepts are repeated across sections, reducing clarity and readability. Considerable condensation and restructuring are needed.
4. The originality of the review is not yet clearly defined. The authors should better explain the specific research gap and the added value of this review compared with existing literature.
5. The distinction between experimental, associative, and clinically established evidence should be improved to avoid overinterpretation.
6. Clinical implications should be better integrated and more explicitly connected to the mechanistic discussion.

 

1. The abstract is generally understandable, but it remains too broad and does not sufficiently clarify the specific rationale, scope, and added value of the review. The authors should make the objective more precise and explicitly state what distinguishes this review from previous literature on MASLD and cardiovascular disease.
2. The introduction provides background information, but the transition from general MASLD concepts to the specific cardiovascular focus could be more concise and better structured. The central research gap should be stated more explicitly.
3. Section 2 contains relevant mechanistic information, but several concepts are repeated across subsections, especially regarding inflammation, insulin resistance, oxidative stress, and endothelial dysfunction. This section would benefit from consolidation and reduction of overlap.
4. The adipokine section and Table 1 are informative, but they remain mostly descriptive and partially repetitive. The table is dense and could be simplified, while the text should focus more on interpretative relevance rather than re-listing the same points.
5. Figure legends, particularly those associated with the mechanistic figures, are too long and in part reproduce textual content. The figures should complement the manuscript rather than function as extended narrative sections. Shorter legends and clearer citation in the main text are recommended.
6. The manuscript would benefit from a clearer distinction between human evidence and experimental/preclinical evidence throughout the text. In several places, mechanistic hypotheses and clinically established implications are discussed in the same tone, which may lead to overstatement.
7. The clinical section is potentially useful, especially regarding screening and integrated assessment, but it should be more tightly connected to the earlier mechanistic discussion so that the review reads as a unified whole rather than as partially separate molecular and clinical parts.
8. Terminology should be checked carefully for consistency. The transition from NAFLD to MASLD should be presented clearly once and then used uniformly throughout the manuscript. All abbreviations should be defined at first appearance.
9. Careful technical editing is needed. There are several language inaccuracies, typographical problems, and reference-list issues that should be corrected before publication, including at least one duplicated reference number.
10. All tables and figures should be explicitly cited in the text before their appearance, and their specific contribution to the argument should be stated more clearly.

Author Response

Dear Reviewer 2,

Thank you for the opportunity to revise our manuscript "The pathophysiological interrelationship between metabolic-dysfunction associated steatosis liver disease and cardiovascular diseases" (Manuscript ID: antioxidants-4223391).

We are grateful to the reviewers for the constructive feedback. We have addressed every comment below and believe the revised manuscript is substantially stronger as a result.

Comment nr. 1. The abstract and introduction address a relevant topic, but they do not yet provide a sufficiently clear and focused description of the specific scope, rationale, and added value of this review. The research gap and the manuscript’s original contribution should be stated more explicitly.

Answer to comment nr. 1: We would like to thank you for this comment! Since we re-edited the entire paper, a new abstract was written. With this new abstract we would like to make a better impact on readers by enlisting the purpose of this relevant topic. We have felt that our originally submitted paper didn,t highlight the main message that this hot topic presents. To give a meaningful and more determined message we have reconstructed the article to raise awareness regarding on the impact of this condition.

Comment nr. 2.  The conclusions are only partially supported by the evidence presented. They tend to overgeneralize mechanistic insights and do not sufficiently reflect the descriptive nature of the review. A more cautious interpretation, with clear distinction between established evidence and emerging hypotheses, is required.

Answer to comment nr. 2:  To better focus on the established evidence and emerging hypothesis we reconstructed the entire paper, providing a better approach to the multiorgan affected complex disease. The paper has been reorganized so the liver-heart axis was molded into one chapter, with this we wanted readers to get a wider view on the pathophysiological processes. To fulfill this desire we focused on common patological pathway – metabolic dysorder – and we added two mechanistic image. One focuses on the topic of the addressed scientific paper - Antioxidants – and the other simplifies the intrahepatic molecular processes. To give a proper solution to the provided suggestion we highlighted separately the preclinical and human studies findings. With this approach we are hoping to fulfilled te suggested problem. To help readers with summarizing the provided evidences we created a separate chapter, which highlights the main conclusions and the near future goals that our Research Group will focus.

Comment nr. 3: The discussion is broad, but its timeliness and scientific qualification are insufficiently supported by a transparent review methodology. In addition, the manuscript would benefit from a more critical appraisal of the evidence and from a clearer distinction between established mechanisms and emerging hypotheses.

Answer to comment nr. 3: this presented topic has a great interest among researchers and clinicians as well. Since this topic has a broad reference, the discussion reflects the vastness of the topic, that,s why at first glance it may seem broad. We tried to narrow the topic by focusing on the common pathophysiological pathways – metabolic dysorder. Not to neglect any of the organs, we tried to balance our presentation by having a neutral approach to the ongoing dialogue between liver and heart. To ensure a clearer distinction between established mechanism and emerging hypothesis, we added substantial informations and reference list on the findings, which we presented in several tables. To better sustain this approach in a newly written chapter, where we presented the pharmacotherapy we enlisted the phase 3 clinical trials to help the reader with novel data. We hope we fulfilled this expectation.

Comment nr. 4: Figures and tables are informative but not optimally presented. Several figures are conceptually overloaded and insufficiently integrated into the text, and their legends are excessively long. Tables are dense and not formatted according to standard three-line table conventions, which reduces readability. Substantial revision of both figures and tables is required.

Answer to comment 4. : To fulfill the given comment, we tried to maintain the provided idea on restructuring the paper. We added easy to read table regarding adipocytokines and hepatokines. We simplified the figures, by adding two extra figures. One added figure simplified the intrahepatic processes, so we made an additional figure, whish isn,t overcrowded with large volume of informations. To better highlight the Antioxidants topic, we created an additional figure insisting on the central role, which antioxidants (glutathione) acts on the oxidative stress process. We are thankfull for your comment.

Major comments:

1. The review addresses a relevant topic, but the review type and methodology are insufficiently defined. The authors should clearly state that this is a narrative review and provide minimal methodological transparency regarding literature search and selection.
2. The manuscript is predominantly descriptive and requires stronger critical synthesis. Mechanisms are extensively listed, but the evidence is not sufficiently prioritized according to robustness and clinical relevance.
3. Redundancy is substantial. Several concepts are repeated across sections, reducing clarity and readability. Considerable condensation and restructuring are needed.
4. The originality of the review is not yet clearly defined. The authors should better explain the specific research gap and the added value of this review compared with existing literature.
5. The distinction between experimental, associative, and clinically established evidence should be improved to avoid overinterpretation.
6. Clinical implications should be better integrated and more explicitly connected to the mechanistic discussion.

Answers to major comments: The authors would like to thank the reviewer step-by step comments. By highlighting the process that requires our work to be published we made changes according to the reviewers comments and suggestions. We would like to submit our answers to the given comments:

1. we have tried from the start to write our review article in a narrative manner. With this presentation method we wanted to raise awareness on this hot topic, so we provided a novel and common view on the increasing number of cases with MASLD and with probable associated comorbidities that may develop, and the high risk factors that can lead to various CVD, that can further worsen the quality of life. By presenting a step-by-step approach we highlighted the multifactorial pathomechanisms that trigger and worsens these conditions. Our main goal is to detect the earlier stages of these conditons so we are going to be able to define the presence of CVD or their probable complications in a timely manner.

 The methodology, which we selected the literature was provided in the text. We tried to give a wide and neutral approach when we listed the reference list. Our main target was to provide the original paper, which the reasearch finding was presented and we added other valuable papers, which presented the main topic, but in other view and format. (e.g. review papers)

2. our presentation is descriptive, but we synthesed the theoretical parts in one easy to read and easy to follow processes. The nature of the chapter – metabolic dysorder – intertwines the several cellular processes, which are identified in the liver and in the heart, making the crosstalks between organs in one chapter. To better highlight the clinical relevance of the presented topic, we created a new chapter, which provides an up-to-date data on relevant pharmacotherapies. To better highlight this informations we added an extra table, where relevant phase 3 clinical trials were presented. Hope that we manage to fulfill this goal.
3. By re-editing the entire paper, we managed to remove the redundant parts. Although we tried to be reasonable, some of the shared ideas between chapters might occur, but this was maintained to help readers to follow the presented information and link chapters together.
4. To better highlight the originality of the paper we created a conclusion and future perspective chapter, where we highlighted the main take home messages of the presented information. Here we shared in a brief manner our Research Group vision on the presented topic, and what our near future research targets are.
5. To better establish the presented evidences we tried to provide substantial reference on the mentioned evidences. Whether they were experimental, associative or clinical importance, after every statement we provided the proper reference. With this approach, we have gave a broader spectrum analysis of the available references.
6. To have a proper clinical impact, we inserted a pharmacotherapy chapter, where we listed all the available informations and up-to-date data on the clinical trials, which were conducted on this topic. Clinicians can identify, what are the probable therapeutical methods and drug categories in various patients.

 

  The authors would like to thank you for the comments, which made our re-edited version a more compact and more easy-to-read publication. We are aware of the vastness of this hot topic, we tried to provide a hollistic overview of this complex pathology. By reconstructing the original paper we focused on the elimination of the redundant parts, and we tried to achieve a balanced and neutral citation method. Probably due to the huge number of publication our reference list is a robust one, but every reference makes the written informations a more valid statements. Even tough our paper was written in a narrative method, we tried to provide a step-by-step approach by listing all the intertwined mechanisms, which leads to appearance of several metabolic-related conditions. To reduce the overcrowded informations in the presented figures and graphics we have made slight improvements by providing two extra images and easy to follow tables. Hope we have managed to fulfill these goals.

 

Best regards,

 

corresponding authors: Dr. Gál, Dr Tóth.

 

Reviewer 3 Report

This is a comprehensive review of the pathophysiological links between MASLD and cardiovascular disease. The authors provide a valuable summary of the inter-organ communication between the liver and the heart. Given that this crosstalk is central to the pathogenesis of both MASLD and cardiometabolic disorders, the manuscript would benefit from a more balanced representation of the bi-directional nature of this relationship. To further strengthen the manuscript and ensure it meets the rigorous standards for publication, I have outlined several suggestions regarding organization, conceptual depth, and accuracy.

1. To improve the clarity and utility of the data presented in Table 1, the following structural changes are recommended:
a. Itemized the effects: The physiological effects of adipokines should be presented in a bulleted or point-by-point format rather than dense text blocks to facilitate quick reference.
b. Biochemical classification: Please include a dedicated column to specify the biochemical type of each adipokine (e.g., protein hormone, glycoprotein, etc.).

2. Figure 1 serves as a visual foundation for your manuscript. To enhance its instructional value, the following suggestions are recommended:
a. Panel labeling: Introduce distinct labels (e.g., A, B, C) for different sections of the figure to correspond directly with descriptions in the figure legend (e.g., "Free fatty acid accumulation" or "Pathophysiological interplay ....").
b. Heart to liver axis: Incorporate visual elements that illustrate how cardiac dysfunction (e.g., reduced cardiac output or systemic congestion) contributes to the progression of MASLD.

3. Content expansion about the disease-related hepatokines. I suggest the authors include a more detailed summary of MASLD-related hepatokines (e.g., Fetuin-A, FGF21, Selenoprotein P). Specifically, discuss how these liver-derived factors drive the pathogenesis of cardiovascular diseases.

4. Addressing the Heart-to-Liver Axis. Currently, the manuscript focuses heavily on the "liver-to-heart" axis. To provide a truly holistic view of organ crosstalk, the author should discuss the following point:
Bi-directional interplay between liver and heart: Discuss the role of heart disease in the pathogenesis of MASLD. For instance, hemodynamic changes or systemic inflammation resulting from heart failure can exacerbate hepatic steatosis and fibrosis. The narrative should reflect a reciprocal relationship rather than a one-way path.

5. Some typo errors require attention to ensure the manuscript's professionalism:
a. Figure 2 legend: Please revise the labels on page 16 (lines 627 and 636), as the current nomenclature appears erroneous.
b. In-text citations: Ensure that Table 1 and Figure 2 are explicitly referenced within the main body of the text, as these citations are currently missing.

6. Please verify and correct the following references to maintain citation integrity:
a. Ref. #28, correct volume and pages to “27:2069-2070” (page 21, line 796).
b. Ref. # 33, correct volume and pages to “41:2313-2330” (page 21, line 807).
c. Ref. #66, standardize the journal abbreviation to “Exp. Ther. Med.” (page 23, line 884).
d. Ref. #128, update the citation metadata to “2026;23:219-238” (page 26, line 1031).
e. Ref. #183, resolve the duplicate numbering to ensure the reference list remains sequential (page 28, lines 1142 and 1145).

The comments have been list in the Major comments.

Author Response

Dear Reviewer 3,

Thank you for the opportunity to revise our manuscript "The pathophysiological interrelationship between metabolic-dysfunction associated steatosis liver disease and cardiovascular diseases" (Manuscript ID: antioxidants-4223391).

We are grateful to the reviewers for the constructive feedback. We have addressed every comment below and believe the revised manuscript is substantially stronger as a result.

Comment nr. 1: To improve the clarity and utility of the data presented in Table 1, the following structural changes are recommended:

1. Itemized the effects: The physiological effects of adipokines should be presented in a bulleted or point-by-point format rather than dense text blocks to facilitate quick reference.
2. Biochemical classification: Please include a dedicated column to specify the biochemical type of each adipokine (e.g., protein hormone, glycoprotein, etc.)

Answer to comment nr 1.: We have re-edited the entire scientific paper. In this way we tried to fully integrate the suggested infromations. We have taken in consideration all the written suggestions, and we have implemented them. To further ensure the interpretability we listed the adipocytokines in an informative table. (Table 2.)

Comment nr. 2: Figure 1 serves as a visual foundation for your manuscript. To enhance its instructional value, the following suggestions are recommended:

1. Panel labeling: Introduce distinct labels (e.g., A, B, C) for different sections of the figure to correspond directly with descriptions in the figure legend (e.g., "Free fatty acid accumulation" or "Pathophysiological interplay ....").
2. Heart to liver axis: Incorporate visual elements that illustrate how cardiac dysfunction (e.g., reduced cardiac output or systemic congestion) contributes to the progression of MASLD.

Answer to comment nr. 2: To further simplify the provided informations, we decided to add a new figure, which exhibits the intrahepatic cellular mechanisms. To label the figures accordingly to the suggested comment we labeled the figures with I, II, III labels. We have tried not to overwhelm the revised figures, instead we provided a more balanced approach by giving a balanced presentation between processes that are occuring in heart-liver axis. These crosstalks mechanism have been written in the text, with this approach we tried to minimalise the redundancy that was present in the previously submitted version. We would like to highlight the fact that in our newer version the 1st figure was moved forward in the text, which is currently the number 3 figure.

Comment nr. 3: Content expansion about the disease-related hepatokines. I suggest the authors include a more detailed summary of MASLD-related hepatokines (e.g., Fetuin-A, FGF21, Selenoprotein P). Specifically, discuss how these liver-derived factors drive the pathogenesis of cardiovascular diseases.

Answer to comment nr. 3: We like to thank you for this comment! According to the given suggestion we added this content, with a brief and informative manner. Hope we managed to fulfill this expectation.

Comment nr. 4: Addressing the Heart-to-Liver Axis. Currently, the manuscript focuses heavily on the "liver-to-heart" axis. To provide a truly holistic view of organ crosstalk, the author should discuss the following point:

Bi-directional interplay between liver and heart: Discuss the role of heart disease in the pathogenesis of MASLD. For instance, hemodynamic changes or systemic inflammation resulting from heart failure can exacerbate hepatic steatosis and fibrosis. The narrative should reflect a reciprocal relationship rather than a one-way path.

Answer to comment nr. 4: We would like to thank you for this valuable suggestions. After a careful consideration, we re-edited the chapters, which covers the pathophysiology background. With this approach we tried to give a balanced manner, presenting in equal size and impact the crosstalks between heart and liver. We wanted to ensure the readers that this disease is not a one organ-based pathology. By presenting this inter-organ dialogue we wanted to present this complex condition in a balanced manner. Our main goal was, to avoid text redundancy as well. We highlighted the inter-reactions that both of the organs pathology have on one another. This negative vitious cycle, that occur between liver-gut-heart can have multiple complications. These negative, probable outcomes were highlighted in the text, so the reader can sense the importance and possible consequences that MASLD can trigger.

Comment nr. 5: Some typo errors require attention to ensure the manuscript's professionalism:

1. Figure 2 legend: Please revise the labels on page 16 (lines 627 and 636), as the current nomenclature appears erroneous.
2. In-text citations: Ensure that Table 1 and Figure 2 are explicitly referenced within the main body of the text, as these citations are currently missing.

Answer to comment nr. 5: Thank you for the listing the mentioned errors. We have try to eliminate and to adjust to the provided informations. We have made major revision, we have tried to improve the readability, we have eliminated the redundant parts and we have restructured the pathophysiology process-related chapter. With these modificatiouns we have tried to further increase the provided informations impact. We hope that the reviewer sees these changes as an improvement, and the concise and restructured format gives a better layout for readers.

Comment nr. 6: Please verify and correct the following references to maintain citation integrity:

1. Ref. #28, correct volume and pages to “27:2069-2070” (page 21, line 796).
2. Ref. # 33, correct volume and pages to “41:2313-2330” (page 21, line 807).
3. Ref. #66, standardize the journal abbreviation to “Exp. Ther. Med.” (page 23, line 884).
4. Ref. #128, update the citation metadata to “2026;23:219-238” (page 26, line 1031).
5. Ref. #183, resolve the duplicate numbering to ensure the reference list remains sequential (page 28, lines 1142 and 1145.

Answer to comment nr. 6: We are greatful for the mentioned reference errors. We have corrected every above mentioned errors, according to the provided suggestions.

Our Research Group and the authors would like to express our appreciation for the helpful and friendly suggestions. Every comment and suggestions were embeded in the new re-edited version. We are truly grateful that we could provide a better structured and an informative, revised scientific paper. We would like to thank you for all the considerations that were provided to us, and we hope that this re-edited version would cover all the expectations. We appreciate the suggestions and the time invested in reviewing our article.

 

Best regards,

corresponding authors: Dr. Gál, Dr. Tóth.

Round 2

Reviewer 1 Report

I thank the Authors for the extensive revision effort. The manuscript has substantially improved compared to the original version, particularly regarding the inclusion of additional mechanistic details, the expanded focus on oxidative stress-related pathways, and the addition of new mechanistic figures linking MASLD and cardiovascular disease. As a consequence, the review is now more comprehensive and better focused on the molecular interplay between MASLD and CVD. However, some issues still deserve further attention before publication.

1. Although the mechanistic discussion has been significantly expanded, some sections remain excessively descriptive and partially redundant. Further condensation and restructuring of selected paragraphs would improve readability and help maintain focus on the central oxidative stress-related mechanisms.

2. The section regarding biomarkers would benefit from a clearer distinction between evidence derived from experimental models and findings validated in human studies, with greater emphasis on translational relevance.

3. The English language still requires careful revision, as grammatical inaccuracies and stylistic inconsistencies remain throughout the manuscript.

Overall, the manuscript has considerably improved and is now much stronger scientifically.

Please carefully revise the English language throughout the manuscript.

Please reduce redundancy in selected mechanistic sections.

Please better distinguish preclinical and clinical evidence, particularly in the biomarker-related sections.

Some tables and mechanistic descriptions could be simplified to improve readability.

Author Response

Dear Reviewer 1,

 

     The Authors would like to thank you for all the valuable contribution that has made the manuscript a better and more impactful version. We have taken in consideration all the written advices, and we express our gratitude for Reviewer 1.

    We are grateful for editors at Antioxidants who encouraged and highlighted problems with the manuscript, and extended time to submit the revised manuscript.

We would like to answer in a concise manner to the provided comments:

1/. We consider that the mechanisticaly presented chapter were considerably shortened and molded together with information from both side of the liver-heart axis. Any further shortening would likely lead to missing informations. Probably this chapters have a didactic presentantion, but we believe this gives a ,,full picture” approach regarding on this hot topic. Most of the evidences that are emerging are in vitro/in vivo based experiments. To avoid overstatement we tried to focus on a more evidence-based approach, where the primary end-points were given to results from clinical trials. To further enhance this approach we seriously rethinked all the afirmations regarding pharmacotherapies. Every affirmation in this section is now sustained by all the available clinical guidelines used by clinicians. We thank you for your helpful comment, but we consider this version gives a better and concise presentation, without withholding any meaningful affirmation on this topic. With our paper we tried to cover every aspect from every angle.

2/. To rule out any misleading information or unsustained conclusions we debated long and hard this issue, and we decided to delete this chapter from the manuscript. The highlighted probable or plausible biomarkers need further research to reach their possible meaning to become clinical biomarkers in everyday medical activity.

3/. We have tried our best to avoid typo errors, misspellings or other punctuation errors. We are grateful for the patience and the helpful comment that raised awareness to fully check the manuscript. Hope we managed to fulfil this goal.

Author Response File: Author Response.pdf

Reviewer 2 Report

The revised manuscript has substantially improved in scope, structure, and clinical orientation. The topic is relevant and timely, and the authors have made meaningful efforts to clarify the liver–heart axis in MASLD. However, several issues still require attention before publication.

1. The distinction between established clinical evidence, associative data, and mechanistic hypotheses still requires strengthening.
   The manuscript now includes a broader discussion of molecular mechanisms, oxidative stress, glutathione depletion, biomarkers, screening, and pharmacological strategies. However, some statements remain too definitive for a narrative review. Claims regarding oxidative stress as the “key connection” between MASLD and CVD, antioxidant-targeted strategies, emerging biomarkers, and bioimpedance-based early detection should be framed more cautiously. The authors should explicitly distinguish mechanisms supported by robust human clinical data from those based mainly on preclinical, experimental, or associative evidence.
2. The narrative review methodology has improved but remains insufficiently transparent.
   The authors now state that this is a narrative review and provide basic information on databases and keywords. Nevertheless, the search strategy should be reported more clearly, including the search timeframe, date of last search, broad inclusion/exclusion principles, and rationale for article selection. A PRISMA flow diagram is not required for a narrative review, but minimal methodological transparency is necessary to support the timeliness and balance of the discussion.
3. Further critical synthesis and prioritization are needed.
   The manuscript remains partly descriptive and encyclopedic. Several sections list pathways, biomarkers, adipokines, hepatokines, experimental findings, and therapeutic targets without consistently explaining their relative clinical importance. The authors should prioritize mechanisms according to evidentiary strength and clinical relevance, emphasizing which pathways have direct implications for cardiovascular risk stratification or management and which remain exploratory.
4. Figures and tables still require substantial refinement.
   Although the revised version includes additional visual material, some tables remain dense and difficult to read, and several figures are still conceptually overloaded. The authors should simplify figures, shorten legends, avoid duplication between figures and tables, and ensure that each visual element is explicitly cited and interpreted in the main text. Tables should be reformatted for readability and should focus on clinically or mechanistically essential information rather than exhaustive detail.
5. The clinical implications should be made more balanced and actionable.
   The sections on screening, biomarkers, pharmacotherapy, and future perspectives are useful, but they should be more clearly separated into established recommendations, emerging approaches, and author-proposed perspectives. In particular, proposed strategies such as broader cardiological screening or bioimpedance-based early MASLD detection should not be presented as ready for routine clinical implementation unless supported by sufficiently validated clinical evidence.
6. Further language and style editing is required.
   The manuscript is understandable, but several grammatical inaccuracies, awkward formulations, typographical errors, and inconsistent terms remain. A final professional scientific language revision is recommended to improve clarity, concision, and readability.

 

1. The title is appropriate and sufficiently specific for a pathophysiology-oriented narrative review. However, please ensure consistency between singular/plural usage: “cardiovascular disease” is preferable to “cardiovascular diseases” if the manuscript is framed around CVD as a disease spectrum.
2. The abstract has improved substantially, but it remains somewhat dense and mechanistically overloaded. Consider shortening it and reducing the number of sequential mechanistic claims. Statements such as “MASLD is a major driver of CVD” and “oxidative stress is a central mechanistic link” should be expressed more cautiously, for example as “MASLD is strongly associated with increased cardiovascular risk” and “oxidative stress may represent an important mechanistic link.”
3. The introduction now identifies the liver–heart axis more clearly, but the added value of the review should be stated in one explicit sentence. The authors should clarify whether the novelty lies in integrating oxidative stress/glutathione biology with cardiovascular risk, in proposing a clinical screening framework, or in summarizing therapeutic implications.
4. The narrative review search strategy should be expanded. Please specify the search timeframe, date of last search, whether language restrictions were applied, how articles were selected, and whether priority was given to human studies, meta-analyses, guidelines, or mechanistic/preclinical studies. This does not need to become a systematic review, but the current description is too limited.
5. The distinction between MASLD, MASH, NAFLD, and NASH should be checked throughout the manuscript. Some legacy terminology is appropriate when referring to older studies, but the authors should explicitly state when older NAFLD/NASH terminology is retained because it reflects the terminology used in the cited literature.
6. The section on chronic low-grade inflammation is relevant, but several mechanistic statements are presented as linear causal chains. Please avoid implying direct causality when the evidence is primarily associative or derived from experimental models. This is particularly important for TLR–NLRP3 activation, hepatokines, adipokines, gut dysbiosis, glutathione depletion, and myocardial remodeling.
7. The tables summarizing experimental findings are informative but too dense. The authors should consider reducing these tables to the most clinically or mechanistically relevant entries and separating human evidence from animal/in vitro evidence. A column indicating “evidence type” and “clinical relevance” would improve interpretability.
8. Table 3 on clinical biomarkers requires revision. Several biomarkers are listed without sufficient explanation of their current clinical validation or practical utility. The table should distinguish routinely available markers from exploratory biomarkers. Terminology and spelling should also be corrected, including “Potential biomarker,” “endogenous nitric oxide synthase,” “homocysteinemia,” and “4-hydroxy-2-nonenal.”
9. The screening section is useful but should be more clearly aligned with current guideline-based practice. The authors should separate established clinical pathways, such as FIB-4-based risk stratification and elastography, from emerging or investigational tools. Recommendations for systematic cardiovascular screening in all MASLD patients should be phrased carefully and linked to risk-based clinical scenarios.
10. The discussion of bioimpedance spectroscopy should be substantially toned down. The authors’ research activity in this area is interesting, but the text currently risks appearing promotional. The manuscript should clearly state the level of validation, the size and nature of clinical cohorts, and the limitations before suggesting future integration into routine practice.
11. The pharmacotherapy section is clinically relevant but should avoid implying that all discussed drug classes are established treatments for the MASLD–CVD continuum. Please clearly distinguish approved therapies, guideline-supported cardiometabolic treatments, investigational agents, and drug combinations that remain hypothetical or under clinical evaluation.
12. Table 4 is valuable but visually overloaded. It should be simplified, reformatted, and checked carefully for consistency of symbols such as “+,” “Ø,” and arrows. The meaning of each symbol should be defined clearly in a footnote. The table would be more useful if it separated hepatic outcomes, fibrosis outcomes, and cardiovascular outcome data in a cleaner format.
13. Figures 1 and 2 help illustrate complex pathways, but the legends remain long and partly duplicate the main text. Please shorten the legends and ensure that each figure is explicitly interpreted in the corresponding section of the manuscript rather than simply inserted as a visual summary.
14. Please check whether the author affiliation and correspondence block is duplicated on the first page. If this duplication is present in the submitted version, it should be corrected before publication.
15. Several language issues remain and should be corrected by professional scientific editing. Examples include awkward phrasing, typographical errors, inconsistent punctuation, and incorrect word forms such as “hightened,” “in his context,” “potencial,” “edogenous,” “superoxid,” “glycin,” and “hidroxydeoxyguanosine.”
16. The conclusion/future perspectives section should be more balanced. It should summarize what is clinically established, what is biologically plausible, and what remains investigational. The authors should avoid presenting antioxidant-based or bioimpedance-based strategies as near-ready clinical solutions unless supported by validated outcome data.
17. Overall, the revised manuscript is improved and addresses several prior concerns, but further revision is required to improve methodological transparency, reduce overstatement, enhance visual clarity, and better separate clinical evidence from emerging mechanistic hypotheses.

Author Response

Dear Reviewer 2,

 

     The Authors would like to thank you for all the valuable contribution that has made the manuscript a better and more impactful version. We have taken in consideration all the written advices, and we express our gratitude for Reviewer 2, who gave us a step-by-step guide to improve the revised manuscript.

    We are grateful for editors at Antioxidants who encouraged and highlighted problems with the manuscript, and extended time to submit the revised manuscript.

    We would like to respond in a concise manner to the detailed comments/remarks that we have received:

1/. We have submitted our paper accordingly to the written remark. In the title we have used ,,cardiovascular disease” as a singular noun. Probably there was an incorcodance in the SUZY system.

2/. We are grateful for the given advises regarding the abstract. We have inserted the recommended words.

3/. We believe that the introduction highlights the liver-heart axis. To give a more impactful meaning we have added the required sentence. To give a more impactful answer to the risen concerns regarding clinical screening framework and therapeutic impications we have improved and detailed the screening and pharmacotherapy chapters. We highlighted our written statements according the available clinical guidelines. To pharmacotherapy section covers an up-to-date information in accordance with the guidelines used in USA and the European Union.

4/. We thank you for the provided insight. To describe a more understandable review method we have added a more detailed informations regarding methods.

5./ The nomenclature issue was covered in the original, submitted paper. We have written that there was a change in nomenclature in 2023. Although the scientific publications we have listed in the reference list use both of the terminology, we used MASLD, as the new terminology throughout the paper, but there are some of terminus technicus that are used even in nowadays literature with the old terminology. e.g. NAFLD activity score (NAS-score). To give the readers a better understanding we inserted the proper reference, in which detailed informations regarding the change of nomenclature can be checked.

6/. The chronic low-grade inflammation chapter represents the didactic approach that was reduced, modified and re-edited thoroughly. We believe the written sentences and every affirmation that was embeded in this chapter are build on a vast number of scientific publications. To avoid misleading interpretations and conclusions we added that some of the conclusions were drawn from in vitro or in vivo experiments. We thank you for highlighting this probable misleading facts.

7/. We revamped the entire table regarding informations about Adipokines. Taking in consideration the given advice, we focused on results emerging from clinical studies that can highlight further scientific researches on this issue.

8/. We have debated intensely the table 3 issue regarding clinical biomarkers. We concluded that there aren,t scientifically proven and used biomarkers, so to avoid misleading interpretation and to shorten the manuscript lenght we decided to rule out this chapter.

9/. We embeded several clinical guidelines into our manuscript. to give a more evidence-based approach we inserted in the proper places the references regarding guidelines. The statements which were written in the screening chapter were checked and improved in accordance with the guidelines that are used by cardiologists, hepatologists.

10/. To avoid self-promoting aspect of our Research Group we have deleted the sentences regarding bioimpedance spectroscopy.

11/. We are grateful for this comment. The pharmacotherapy section has improved, we inserted the guideline-supported and approved therapies, and we clarified the raised issue regarding drug combinations. Regarding the probable and plausible drug combination section we have provided information concerning the investigational nature or combinations that are under clinical evaluation during clinical trials.

12/. We have totally reconsidered and rebuild the tables considering hepatic- and cardiovascular outcomes. We have simplified the column according to the given advice, and we thank you for this useful and helpful comment.

13/. We have inserted several parts where the reader can check the Figures (1,2) and we have shorten the legends, we checked the text to avoid repeating the same abbreviations in the text in the legends.

14/. We checked the affiliation list, it seems, that when we submitted our manuscript in the 2nd round, we changed to order of authors, and somehow the system duplicated the original author list with the newly submitted version. We hope that this time this problem will be avoided. Thank you again for raising this unconvenience.

15/. Several mentioned language issues were corrected, the core amount of the mentioned issues were related to the clinical biomarker chapter, which was deleted in this new version.

16/. We believe that with the added new informations managed to improve and clarify the manuscript. To not overextent the manuscript lenght we have taken every mentioned aspect in consideration. In the conclusion section we have deleted the bioimpedance spectroscopy statement, because although we consider as an emerging screening tool, there aren,t impactful evidences to be embeded in everyday evidence-based medical screening method.

Overal we tried our best to improve the newly submitted manuscript. We have taken every detailed comment in consideration and we have tried our best to give the proper answers to the risen problems. We focused on the evidence-based approach, and we have tried to tone down conclusions which were given from several in vitro/in vivo experiments. We truly hope that we have managed to fulfil this goal.

 

Author Response File: Author Response.pdf

Reviewer 3 Report

The revised manuscript comprehensively addresses the concerns raised during the previous review cycle. Significant improvements in clarity, conciseness, and overall scholarly quality have been implemented, rendering the work suitable for publication in Antioxidants.

As in Major comments.

Author Response

Dear Reviewer 3,

 

The authors would like to express gratitude for your constructive approach!

With this letter we would like to summarize the improved and revised manuscript in a point-by-point format:

1/. We extended and improved the research method strategy that was used in creating the manuscript.

2/. We inserted reference that covers the newly used nomenclature.

3/. We embeded in the mechanistic presented chapters sentences that clarifies that some of the statements and conclusions were drawn from several in vitro/in vivo experiments.

4/. We redesigned the adipokines table, where our main focus was on the clinical trial approach.

5/. We debated the issue with the clinical biomarker chapter. We decided to rule out this chapter from the manuscript, because further research are needed to clarify every aspect of the plausible and probable biomarkers to be used in everyday clinical practice.

6/. We have given extra content to the pharmacotherapy chapter. Here we inserted evidence-based informations. In this chapter we have simplified the hepatic- and cardiovascular-related outcome table and we improved the table regarding phase 3 clinical trial. Our main target was to provide sufficient evidence to sustain every affirmation that were mentioned in the screening and in the drug therapy chapters. To further improve this important chapter we have given clarifying informations on the probable drug combination, because some of them are in clinical trial phase and there are some which are plausible, but without clinical evidence.

With this newly submitted manuscript we tried our best to clarify every hot topic, raising awareness on the clinical side. Our target was to give a better understanding and to sustain every affirmation from clinical guidelines.

We wish to thank you again for your constructive approach to our submitted and revised manuscript. 

Author Response File: Author Response.pdf