Genetic Insights into Acne, Androgenetic Alopecia, and Alopecia Areata: Implications for Mechanisms and Precision Dermatology

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Interesting review. Add limitations of the use of genetics in clinical practice as a new section. Provide several limitations and explain how they could be solved

Author Response

Comments 1: Interesting review. Add limitations of the use of genetics in clinical practice as a new section. Provide several limitations and explain how they could be solved.

Response 1: We agree with the reviewer on the importance of critically discussing current limitations. To address this, we reorganised the discussion and conclusion to incorporate explicit paragraphs on incomplete variance explained by GWAS, ancestry portability, functional interpretation gaps, and the lack of clinical consensus for implementation. We also emphasised possible solutions, including larger multi-ethnic studies, functional follow-up, and prospective validation. We opted not to add a standalone “limitations” section, as this would have substantially lengthened the manuscript; instead, we integrated these considerations into the final sections to preserve flow and readability while fully addressing the reviewer’s request.

 

Reviewer 2 Report

Comments and Suggestions for Authors

Torres de Souza presents a critical review of current knowledge on genetic variant analyses related to pathological states of the hair follicle and sebaceous glands, with a particular focus on androgenetic alopecia (AGA), alopecia areata (ARA), and acne. The manuscript usefully synthesizes evidence from large genome-wide association studies (GWAS), highlighting potential interrelationships between metabolic pathways implicated in these conditions. The declared aim is to promote the use of genetic insights to enhance therapeutic efficacy through personalized interventions tailored to the gene variant sensitivities of individual patients. At the same time, the author proposes extending this approach to cosmetic interventions, not only to prevent or mitigate the onset of the conditions under consideration, but also to sustain restored healthy states. Overall, the review emphasizes the advantages of a genetics-based approach in addressing hair follicle and sebaceous gland disorders through dermatological treatments that leverage synergies between cosmetic and pharmacological interventions, with the overarching goal of prioritizing patient benefit over traditional boundaries between these domains.

The manuscript is of great interest to the field, well written, and contains noteworthy elements of originality. The language used is consistent with the high scientific level of the journal, and the presentation of the arguments is clear and logically consistent. My main concerns relate to the figures, which in my opinion could be improved to better guide the reader through the author’s interpretative proposal, particularly as it involves some complex and at times non-obvious steps.

 

Suggested major revisions

Figure 1. The diagram is intended to highlight the interconnections between genes involved in different functional areas of skin metabolism and its adnexal organs. Although the caption helps the reader follow the proposed inferences, the use of colors could make the scheme easier to understand — for example, by assigning different background colors to the text boxes according to the predominant functional pathway, as interpreted by the author. Likewise, the color of the connectors could be differentiated depending on whether they indicate a stimulatory effect (e.g., green) or an inhibitory one (e.g., red) on the functional target of the gene.

It should also be noted that the text box “tight junctions” does not appear, in my view, to be fully consistent with the argument presented, and this also applies to the corresponding discussion in the text. As indicated in some of the cited references, OVOL1 is primarily a regulatory factor that drives keratinocyte differentiation by promoting the synthesis of cornified envelope proteins, especially filaggrin and loricrin, rather than regulating tight junction formation. Similarly, filaggrin itself, also included in the scheme, contributes mainly to the composition of the protein–lipid matrix of the stratum corneum and, secondarily (through enzymatic breakdown), to the generation of natural moisturizing factors within corneocytes. It would therefore be more appropriate to replace “tight junctions” with “skin barrier functionality.

Figure 2. In my view, this figure does not effectively convey the information the author intends to communicate. If I understand correctly, the vertical alignment of the markers on the left is meant to correspond functionally to those on the right, but this relationship is far from intuitive. All the blue factors on the left are connected to the functional hubs at the center, whereas only four of the factors on the right are connected to hubs different from those on the left. Consequently, synergistic activities are not readily apparent, and the interactions among the central hubs are unclear, as some are linked by a connector while others are not.

Apoptosis control is depicted as quite isolated, despite is an intrinsic aspect of the follicle cycling process and of all skin tissue renewal functions (therefore intrinsic to morphogenesis). My suggestion would be to redesign the figure to more clearly highlight the shared involvement of the various markers as biochemical bridges among the identified functional pathways.

 

Suggested minor changes

1. All scientific names, including those in the references, should be italicized in accordance with the International Nomenclature Codes.
2. Line 51. The term 'intervention' is, of course, correct; however, in this context I would consider replacing it with 'treatment.
3. In this context (e.g., line 118), the term 'programs' may be less precise than 'pathways.' I suggest considering the use of 'pathways' to better reflect the biological processes being described.
4. "damage" could be clearer than “compromise”
5. This reaction is unclear. FADS2 converts palmitic acid (16:0) to sapienic acid (16:1 n-10). Linoleic acid (18:2) is not the natural precursor of sapienic acid, as it contains 18 carbons and two double bonds. Please clarify the pathway or correct the figure/text accordingly.
6. Line 188. This sentence appears cryptic. I assume you are referring to the connectors schematized in Fig. 1, but this is not evident. It would be clearer to say: 'WNT–lipid interactions provide an additional mechanistic bridge.'
7. Line 225-227. This sentence is comprehensible, but the language is not always precise. Please consider the following alternative: "From a translational perspective, these studies provide two immediate applications. First, they highlight targetable biological pathways, such as WNT regulators and lipid enzymes, which can guide mechanism-matched interventions and complementary cosmetic strategies (or treatments).
8. Line 227. The expression 'replicated acne locus' is unclear. Literally, it could be interpreted as implying the existence of a gene called 'acne,' which is not the intended meaning. Furthermore, while OVOL1 variants can be associated with a predisposition to acne, the dysregulation of this gene is more commonly known for associations with other disorders.
9. Line 286-289. This statement is supported by [55,56] at the end of the following sentence? it would be better to report the related reference here.
10. Line 519-519 The structure of this sentence is not clear, as it appears to be oriented toward an implied interlocutor.
11. Line 657. I would suggest rephrasing as follows: …with supportive treatments aimed at improving skin barrier function and lipid metabolism to prolong remission.
12. Please check the attached pdf with notes for other very minor suggestions.

Comments for author File: Comments.pdf

Author Response

Comments 1: Figure 1. The diagram is intended to highlight the interconnections between genes involved in different functional areas of skin metabolism and its adnexal organs. Although the caption helps the reader follow the proposed inferences, the use of colors could make the scheme easier to understand — for example, by assigning different background colors to the text boxes according to the predominant functional pathway, as interpreted by the author. Likewise, the color of the connectors could be differentiated depending on whether they indicate a stimulatory effect (e.g., green) or an inhibitory one (e.g., red) on the functional target of the gene.
It should also be noted that the text box “tight junctions” does not appear, in my view, to be fully consistent with the argument presented, and this also applies to the corresponding discussion in the text. As indicated in some of the cited references, OVOL1 is primarily a regulatory factor that drives keratinocyte differentiation by promoting the synthesis of cornified envelope proteins, especially filaggrin and loricrin, rather than regulating tight junction formation. Similarly, filaggrin itself, also included in the scheme, contributes mainly to the composition of the protein–lipid matrix of the stratum corneum and, secondarily (through enzymatic breakdown), to the generation of natural moisturizing factors within corneocytes. It would therefore be more appropriate to replace “tight junctions” with “skin barrier functionality.

Response 1: We thank the reviewer for these insightful suggestions, which we found very valuable for improving Figure 1. The figure was re-designed in Cytoscape using the same underlying dataset and statistical framework but restructured to follow the reviewer’s recommendations precisely. Background colours were added to distinguish the major functional pathways, and connector colours were implemented to reflect functional relationships (green for stimulatory, red for inhibitory, grey for modulatory). As recommended, the label “tight junctions” was replaced with “skin barrier functionality,” which more accurately reflects the biology of OVOL1 and FLG. The figure legend was also rewritten accordingly. We believe these changes substantially enhance both the accuracy and readability of the figure.

Comments 2: Figure 2. In my view, this figure does not effectively convey the information the author intends to communicate. If I understand correctly, the vertical alignment of the markers on the left is meant to correspond functionally to those on the right, but this relationship is far from intuitive. All the blue factors on the left are connected to the functional hubs at the center, whereas only four of the factors on the right are connected to hubs different from those on the left. Consequently, synergistic activities are not readily apparent, and the interactions among the central hubs are unclear, as some are linked by a connector while others are not.
Apoptosis control is depicted as quite isolated, despite is an intrinsic aspect of the follicle cycling process and of all skin tissue renewal functions (therefore intrinsic to morphogenesis). My suggestion would be to redesign the figure to more clearly highlight the shared involvement of the various markers as biochemical bridges among the identified functional pathways..

Response 2: We thank the reviewer for highlighting these issues, which we agree limited the clarity of the original Figure 2. The figure was fully re-designed with a new architecture to better reflect the shared involvement of the pathways. Apoptosis was explicitly integrated with follicle cycling and morphogenesis to prevent its isolated appearance. Additional hub-to-hub connectors were added to clarify the relationships among central processes, including follicle cycling, morphogenesis, immune privilege, and IFN-γ signalling. The distribution of AGA and AA nodes was also reorganised so that their synergistic activities and biochemical bridges are more clearly visible. These modifications make the figure substantially clearer and address the reviewer’s concerns directly.

Comment 3: The reviewer suggested a series of minor textual revisions, including italicisation of scientific names, clarification of biochemical pathways, rephrasing of ambiguous terms, improved precision of phrasing, and supporting references.

Response 3: We thank the reviewer for this careful attention to detail. All minor comments were addressed systematically. Specifically, all occurrences of C. acnes were italicised to comply with nomenclature standards; the description of FADS2 was corrected to indicate that sapienic acid derives from Δ6-desaturation of palmitic acid, while linoleic acid desaturation produces γ-linolenic acid; ambiguous or imprecise terms such as “replicated acne locus” and “programs” were revised; references were added where suggested; and several sentences were rephrased for clarity, including the conclusion, which was adjusted to remove the impression of an interlocutor. We also reviewed the annotated PDF and implemented all additional small corrections. Collectively, these edits improved both the precision and readability of the manuscript.

 

Reviewer 3 Report

Comments and Suggestions for Authors

It is well written, but this manuscript will not be of very high interest to the average clinician. The translational perspective of this work is heavily based on the basic science end of that spectrum. The findings can only really be assumed to be therapeutically relevant, at best. The manuscript needs to be shortened significantly

Author Response

Comments 1: “It is well written, but this manuscript will not be of very high interest to the average clinician. The translational perspective of this work is heavily based on the basic science end of that spectrum. The findings can only really be assumed to be therapeutically relevant, at best. The manuscript needs to be shortened significantly.”

Response 1: We thank the reviewer for these thoughtful remarks. We acknowledge that the review is primarily oriented toward mechanistic and genetic perspectives, which may limit direct clinical applicability at present. However, we believe that providing this mechanistic foundation is essential for informing future translational studies and personalised therapeutic strategies. While a major reduction in length was not feasible without losing necessary context, we carefully revised the structure to improve readability and accessibility. Specifically, sentences and paragraphs were shortened or simplified where possible, and transitions were smoothed to improve flow. We also added explicit discussion of the current translational limitations of genetic findings, including incomplete predictive power, uncertainty of functional interpretation, and the lack of prospective clinical validation, so as to balance enthusiasm with caution. These adjustments aim to make the manuscript more concise, approachable, and clinically relevant while preserving its core purpose as a bridge between genetic discovery and dermatological translation..

 

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

No further comments from my standpoint. The changes made in response to my comments are fine