Review Reports - Breast Cancer and Metabolic Dysfunction-Associated Steatotic Liver Disease

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This is a comprehensive and well written review on the topic MASLD and breast cancer . The different possible links between the conditions are extensively described in terms of epidemiological and statistical relevance, mechanistic insights and possible therapeutic implications . Overall I believe that the manuscript deserves publication. Nevertheless I would like that the authors considered including some information on the possible role of steroid hormones ( glucocorticoids and aldosterone ) in the development of MASLD. I stepped in a paper by Barigou e al ( Biomedicines 2025) that refers to this possible mechanisms and underlines the role of Sgk1 in steroid dependent MASLD. Since Sgk1 is also regulated by insulin and has a growing attention in the field of insulin resistance, it is also involved in inflammation, cell survival and chemo resistance, I feel that the authors could add a little paragraph on this topic, analyzing the possible role of Sgk1 in MASLD and breast cancer

Author Response

Response: In response to the suggestion, we have incorporated a new paragraph discussing the potential role of steroid hormones, particularly glucocorticoids and aldosterone, in the development and progression of MASLD. We specifically addressed the emerging role of serum- and glucocorticoid-regulated kinase 1 (SGK1) as a downstream mediator linking steroid signaling, insulin resistance, inflammation, and metabolic dysfunction. (Lines 328-351)

Reviewer 2 Report

Comments and Suggestions for Authors

Dear editor and authors,

The manuscript addresses a highly relevant and timely topic, exploring the relationship between metabolic dysfunction-associated steatotic liver disease (MASLD) and breast cancer. The review is generally well-organized and scientifically engaging, and it succeeds in integrating epidemiological and mechanistic evidence into a coherent narrative. In particular, the discussion regarding hepatokines such as FGF21, Fetuin-A, and ANGPTL8 adds novelty and translational interest to the manuscript. The figure and summary table also help illustrate the proposed biological interactions. Overall, the topic is important and potentially impactful given the increasing global burden of both MASLD and breast cancer. However, several important issues should be addressed before the manuscript can be considered for publication.

Major Comments

While the association between MASLD and breast cancer is presented clearly, the discussion sometimes gives the impression of a direct causal relationship. Since most of the currently available evidence is observational, I think the manuscript would benefit from a more cautious interpretation in some sections. In particular, it remains difficult to separate the independent effect of MASLD from the broader metabolic environment, including obesity, insulin resistance, and menopausal status.
The epidemiological studies included in the review are quite heterogeneous in patient populations, MASLD definitions, diagnostic methods, and confounder adjustment. I think a short paragraph discussing this heterogeneity and its potential effects on data interpretation would strengthen the review considerably.
The mechanistic sections are generally very good and easy to follow. The discussion around insulin resistance and FGF21 is especially well developed. However, some other aspects, particularly immune modulation and tumor microenvironment interactions, are discussed more briefly. Expanding these areas slightly would help provide a more balanced mechanistic overview.
The hepatokine section is one of the most interesting parts of the manuscript. At the same time, I would suggest slightly softening some statements regarding the translational role of FGF21, Fetuin-A, and ANGPTL8. Although these molecules are promising, much of the evidence remains experimental, and their clinical utility in breast cancer has yet to be established.
Another point that may warrant further discussion is whether different stages of MASLD have distinct oncologic implications. The manuscript mainly discusses MASLD as a single entity, whereas simple steatosis, steatohepatitis, and advanced fibrosis may have very different inflammatory and metabolic profiles.
The clinical implications section could also be expanded slightly. Since the review emphasizes the role of metabolic dysfunction, it would be interesting to discuss whether interventions targeting MASLD or metabolic health (e.g., weight loss, lifestyle interventions, GLP-1 agonists) may influence breast cancer outcomes in the future.

Minor Comments

Several minor typographical and formatting errors should be corrected throughout the manuscript. Examples include: “Traslational Research Unit” instead of “Translational Research Unit,” “biomarke” instead of “biomarker,” and occasional inconsistencies in citation formatting and spacing.
The conclusion is well written overall, but somewhat repetitive of earlier sections. It may be strengthened by ending with a more focused translational perspective or clearer future clinical direction.

Comments for author File: Comments.pdf

Author Response

Major Comments

While the association between MASLD and breast cancer is presented clearly, the discussion sometimes gives the impression of a direct causal relationship. Since most of the currently available evidence is observational, I think the manuscript would benefit from a more cautious interpretation in some sections. In particular, it remains difficult to separate the independent effect of MASLD from the broader metabolic environment, including obesity, insulin resistance, and menopausal status.

Response: We agree that the currently available evidence is predominantly observational and does not allow definitive conclusions regarding causality. In response, we revised several sections to adopt a more cautious and balanced interpretation of the relationship between MASLD and breast cancer. (Lines 17-20, 65, 66, 93-98, 108-113, 179-184, 194-199, 263, 264, 483-485)

The epidemiological studies included in the review are quite heterogeneous in patient populations, MASLD definitions, diagnostic methods, and confounder adjustment. I think a short paragraph discussing this heterogeneity and its potential effects on data interpretation would strengthen the review considerably.

Response: A new paragraph discussing heterogeneity in patient population and its potential effects on data interpretation. (Lines 148-158)

The mechanistic sections are generally very good and easy to follow. The discussion around insulin resistance and FGF21 is especially well developed. However, some other aspects, particularly immune modulation and tumor microenvironment interactions, are discussed more briefly. Expanding these areas slightly would help provide a more balanced mechanistic overview.

Response: Additional information regarding immune modulation and tumor microenvironment interactions was incorporated into the mechanistic sections. (Lines 289-296, 320-326, 369-378, 399-406, 428-435)

The hepatokine section is one of the most interesting parts of the manuscript. At the same time, I would suggest slightly softening some statements regarding the translational role of FGF21, Fetuin-A, and ANGPTL8. Although these molecules are promising, much of the evidence remains experimental, and their clinical utility in breast cancer has yet to be established.

Response: The corresponding sections were revised to soften statements regarding the translational and clinical utility of FGF21, Fetuin-A, and ANGPTL8, emphasizing that current evidence remains largely experimental and requires prospective validation. (Lines 445,446, 451-455, 457-459, 463, 464, 472-474, 490, 491, 496-498, 503-513)

Another point that may warrant further discussion is whether different stages of MASLD have distinct oncologic implications. The manuscript mainly discusses MASLD as a single entity, whereas simple steatosis, steatohepatitis, and advanced fibrosis may have very different inflammatory and metabolic profiles.

Response: A new subsection discussing the potential differences between simple steatosis, steatohepatitis, and advanced fibrosis in terms of inflammatory, metabolic, and oncologic profiles was added. (Lines 231-261)

The clinical implications section could also be expanded slightly. Since the review emphasizes the role of metabolic dysfunction, it would be interesting to discuss whether interventions targeting MASLD or metabolic health (e.g., weight loss, lifestyle interventions, GLP-1 agonists) may influence breast cancer outcomes in the future.

Response: We expanded the clinical implications section by incorporating a brief discussion on the potential impact of metabolic interventions, including weight loss, lifestyle modification, and GLP-1 receptor agonists, on future breast cancer outcomes in patients with coexisting MASLD. Recent PubMed-indexed studies were also added to support this section. (555-575)

Minor Comments

Several minor typographical and formatting errors should be corrected throughout the manuscript. Examples include: “Traslational Research Unit” instead of “Translational Research Unit,” “biomarke” instead of “biomarker,” and occasional inconsistencies in citation formatting and spacing.

Response: The manuscript was carefully revised to correct typographical, formatting, and terminology inconsistencies throughout the text.

The conclusion is well written overall, but somewhat repetitive of earlier sections. It may be strengthened by ending with a more focused translational perspective or clearer future clinical direction.

Response: The conclusion section was revised and expanded to provide a more focused translational perspective and clearer future clinical directions. (Lines 607-650)