Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript provides a comprehensive and up-to-date narrative review on the repurposing of topical metformin for dermatological applications. The topic is timely and clinically relevant, and the authors successfully integrate preclinical and clinical evidence across a wide range of skin conditions, including wound healing, photoaging, inflammatory dermatoses, pigmentary disorders, skin cancer, acne, and hair growth. The review is generally well structured, and the mechanistic discussion, particularly regarding AMPK-mediated pathways, inflammation, oxidative stress, and metabolic regulation, is scientifically sound and well supported by the cited literature.

To further improve the manuscript, some refinements are recommended. First, several sections adopt a predominantly descriptive tone; greater critical synthesis would strengthen the review, particularly by more clearly distinguishing between robust evidence and preliminary or exploratory findings. This is especially relevant given that much of the available data remains preclinical. Second, some mechanistic explanations—most notably those related to AMPK activation—are reiterated across multiple sections and could be streamlined to reduce redundancy and improve readability. Finally, while the limitations are appropriately acknowledged, the conclusions could be slightly more conservative in framing the translational readiness of topical metformin, emphasizing more explicitly the current gaps in clinical evidence and standardization.

Overall, the manuscript represents a solid contribution to the field and would benefit from targeted revisions rather than substantial restructuring.

Comments on the Quality of English Language

The overall quality of English is good and the manuscript is understandable throughout. However, several sentences are overly long and complex, which occasionally affects clarity and flow. Minor grammatical inconsistencies and stylistic repetitions are present, particularly in the more descriptive sections. A focused language and style revision is recommended to improve conciseness, readability, and overall fluency, but no major rewriting is required.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Comments and Suggestions for Authors

The manuscript provides a comprehensive and up-to-date narrative review on the potential role of topical metformin in dermatology, with a particular focus on inflammatory, pigmentary, regenerative, and neoplastic skin conditions. The authors summarize the current understanding of the molecular mechanisms involved, including AMPK activation and modulation of inflammatory, oxidative, and metabolic pathways, and integrate experimental findings with the available clinical evidence. The topic is timely and clinically relevant, the manuscript is generally well structured, clearly written, and supported by an extensive and current bibliography.

Although the manuscript is presented as a narrative review, the description of the literature search in the Materials and Methods section includes several elements commonly associated with systematic reviews, such as a defined time frame, inclusion and exclusion criteria, and the reporting of the number of identified and selected studies. Considering the growing body of literature on topical metformin and the clinical relevance of the topic, the authors could have considered conducting a fully systematic review following established guidelines, such as PRISMA, which would have further strengthened the methodological rigor and reproducibility of the work. If the authors choose to maintain a narrative approach, a clearer justification of this choice and a more explicit distinction from a systematic review would improve transparency and avoid potential misunderstanding by readers.

A substantial proportion of the evidence discussed, particularly in the sections on skin cancer, photoaging, and hair growth, is derived from preclinical studies. While the mechanistic rationale is well developed, the manuscript occasionally conveys an optimistic impression regarding clinical applicability. A clearer distinction between preclinical findings and clinical evidence, especially in the Discussion and Conclusions, would help avoid overinterpretation and improve balance.

Another important point concerns the marked heterogeneity of topical formulations and metformin concentrations reported in the literature, ranging from approximately 0.6% to 30%. In this context, a brief comment on how such variability may affect skin penetration, tolerability, and comparability between studies would further strengthen the translational perspective of the review.

The section addressing skin cancer is scientifically interesting but is exclusively based on in vitro and animal studies. Explicitly stating this limitation within the section itself would help frame these data as preliminary and exploratory rather than as evidence supporting clinical use.

From a stylistic perspective, some sections, particularly those on wound healing and hair growth, are relatively long and could benefit from moderate condensation to reduce repetition. Overall, the English language is clear and appropriate and does not require major revision. Nevertheless, a final round of careful proofreading is recommended to correct minor typographical and formatting inconsistencies observed in the text, such as missing spaces before reference citations (e.g., “human dermal fibroblasts[6]”), inconsistent use of “in vitro/in vivo” notation, and non-uniform formatting of percentages (e.g., “30 %” versus “30%”).

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 3 Report

Comments and Suggestions for Authors

In this review manuscript, Döll-Boscardin et al. present a competently written overview of the use of topical metformin in dermatological settings. Whilst this topic is timely and relevant due to the clear translational interest, there are some concerns which need to be addressed prior to acceptance of the manuscript.

Major concerns:

• Although the authors present a detailed and well covered overview of the effects of metformin in various dermatological settings, there is a lack of description of any potential limitations within the studies (i.e. whether there was a small sample size, or non-randomised designs or short follow ups).
• The abstract, methods, and conclusions all collectively emphasise the need for well designed randomised trials with standardised formations, however, it would be of benefit to briefly discuss potential safety or practical issues associated with the use of metformin in different settings – ideally in a separate subsection.
• The methods mentions the use of recognised guidelines for narrative review synthesis, however these are not specified.

Minor concerns:

• Whilst the methods describing the search process were generally well described, it would be of benefit to describe in more detail certain aspects such as whether any formal assessments of study criteria, quality, or potential risk of bias were conducted.
• Due to the fact that many of the biological mechanisms across different pathologies are conserved, and the review is very text heavy, it would be of potential benefit to include a summary diagram (or diagrams) describing the biological mechanisms either in all pathologies or in individual ones.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf