Skin Cancer Prevention and Antiaging: Role of Nicotinamide

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

In the manuscript “Skin Cancer Prevention and Antiaging: Role of Nicotinamide” the authors provide a comprehensive and clinically relevant overview of nicotinamide role in dermatology. The study lies in its ability to bridge the gap between NAM biochemical function as a NAD+ precursor and its efficacy. Furthermore, the authors offer a well-structured analysis of topical versus systemic administration, supported by clinical trials and recent literature, making it a valuable resource for understanding non-invasive strategies.

 

The manuscript is valuable, however some issue should be addressed.

 

The manuscript provides in the introduction an overview of the mechanisms through which UV radiation induces DNA damage and cutaneous immunosuppression, ultimately leading to non-melanoma skin cancer (NMSC). However, it lacks an updated clinical and molecular framework regarding the broader spectrum of photodamage and its progression toward skin carcinogenesis. Although the authors focus on NMSCs as the most common age-related malignancies, the biochemical mechanism of action of Nicotinamide (NAM) is transversal. UV-induced damage remains the primary driver for skin photodamage and melanomagenesis as well, and this connection should be addressed.

 

The article frequently mentions the risk of skin cancer in vulnerable populations and the necessity for preventive strategies. I suggest expanding the discussion on personalized prevention by integrating the role of NAM with the patient’s genetic background (phenotype/genotype). Indeed, photoaging manifests differently depending on individual biological factors and genetic susceptibility.

 

Furthermore, NAM possesses antimicrobial properties and regulates the epidermal barrier, which significantly influences the skin microbiome.

 

As the current clinical evidence remains fragmented, highlight the major limitations of the cited studies.

 

Please, correct Table 2 with references on the right.

Author Response

Reviewer #1

Comment 1: The manuscript provides in the introduction an overview of the mechanisms through which UV radiation induces DNA damage and cutaneous immunosuppression, ultimately leading to non-melanoma skin cancer (NMSC). However, it lacks an updated clinical and molecular framework regarding the broader spectrum of photodamage and its progression toward skin carcinogenesis. Although the authors focus on NMSCs as the most common age-related malignancies, the biochemical mechanism of action of Nicotinamide (NAM) is transversal. UV-induced damage remains the primary driver for skin photodamage and melanomagenesis as well, and this connection should be addressed.

Response: We thank the Reviewer for this comment. We revised the Introduction to include additional sentences linking chronic photodamage, photoaging, and skin carcinogenesis. We also added a brief text addressing the overlap between chronic UV-induced damage and melanomagenesis, while clarifying that the review primarily focuses on NMSCs, for which the strongest clinical evidence supporting nicotinamide-based prevention is currently available. These modifications have been incorporated into the revised Introduction (pag. 2, lines 59-68 and lines 79-85).

 

Comment 2: The article frequently mentions the risk of skin cancer in vulnerable populations and the necessity for preventive strategies. I suggest expanding the discussion on personalized prevention by integrating the role of NAM with the patient’s genetic background (phenotype/genotype). Indeed, photoaging manifests differently depending on individual biological factors and genetic susceptibility.

Response: We thank the Reviewer for this valuable suggestion. We expanded the Discussion to address interindividual variability in susceptibility to skin carcinogenesis, including the potential contribution of genetic and metabolic factors (paragraph 6.3)

 

Comment 3: Furthermore, NAM possesses antimicrobial properties and regulates the epidermal barrier, which significantly influences the skin microbiome.

Response: We thank the Reviewer for this comment. We have added some sentences in the Result section (paragraph 4.2) addressing the potential effects of NAM on epidermal barrier function and cutaneous homeostasis, while clarifying that clinical evidence on microbiome modulation remains limited.

 

Comment 4: As the current clinical evidence remains fragmented, highlight the major limitations of the cited studies.

Response: We thank the Reviewer for this comment. We have addressed this point by adding a dedicated “Main limitations” column in all three tables summarizing the included studies, to clearly highlight the main methodological and clinical limitations. In addition, we expanded the section 6.3 “Limitations, safety considerations, and future directions” by providing a more explicit critical appraisal of the available literature.

 

Comment 5: Please, correct Table 2 with references on the right.

Response: We thank the Reviewer for this comment. Table 2 has been corrected and improved for clarity. In particular, we have revised the table layout by ensuring proper alignment of the references and added two new columns summarizing statistical analysis and study limitations, in order to enhance readability and facilitate interpretation of the included studies.

Reviewer 2 Report

Comments and Suggestions for Authors

This manuscript is well writen and has timely reviewed the current knowledge on the role of nicotinamide at the intersection of skin aging and non-melanoma skin cancer prevention. The central thesis, that NAD+ depletion is a common mechanistic node linking photoaging and carcinogenesis, is compelling and clearly argued. The manuscript provides a balanced overview of the biological rationale, preclinical data, and clinical evidence for both systemic and topical usages of NAM. The manuscript makes a valuable contribution to the field by linking skin aging and cancer prevention through NAD+ biology.

Author Response

Comment 1: This manuscript is well written and has timely reviewed the current knowledge on the role of nicotinamide at the intersection of skin aging and non-melanoma skin cancer prevention. The central thesis, that NAD+ depletion is a common mechanistic node linking photoaging and carcinogenesis, is compelling and clearly argued. The manuscript provides a balanced overview of the biological rationale, preclinical data, and clinical evidence for both systemic and topical usages of NAM. The manuscript makes a valuable contribution to the field by linking skin aging and cancer prevention through NAD+ biology.

Response: We sincerely thank the Reviewer for the positive evaluation of our manuscript and for recognizing the relevance and clarity of the central thesis linking NAD⁺ depletion, skin aging, and non-melanoma skin cancer prevention. We are grateful for the constructive appreciation of the work.

 

 

Reviewer 3 Report

Comments and Suggestions for Authors

A tremendous amount of work went into preparing this article, supported by the most up-to-date literature (including 2026). Section 2 is noteworthy, demonstrating the wide range of NAM functions that perfectly fit into the role of this compound in aging and carcinogenesis. This section allows all subsequent sections to form a very interesting, logical whole.

Table 1 is very well-constructed, enriched with key findings, and concisely presents a wealth of information. However, confirmation of which of the presented effects are statistically significant is lacking.

Despite these mostly positive impressions, working with this amount of knowledge somewhat diminishes clarity and readability of presentation. First and foremost, describing some of the studies, conducted worldwide, in the text and presenting subsequent studies in Tables, which are not discussed in the text, creates an impression of data overload and a certain chaos. Tables should present data related to studies that are discussed in more detail in the text. Furthermore, in most cases described throughout the paper, the assessment of the significance of the results is omitted.

The cognitive value and readability of the work would be greatly enhanced by the authors' selection of material and their focus on a more detailed discussion of the results, including statistical evaluation of even insignificant ones. After reading the current version of the work, drawing conclusions is extremely difficult.

Other comments:

 - Figure 2 requires correction – its content should imply (as described) that NAM supplementation maintains the NAD+ pool and, consequently, supports DNA repair processes, reduces inflammation, and oxidative stress. In the current version, this consequence is not apparent from the graphical portion of the figure. However, it does imply that NAM induces a decrease in NAD⁺ levels, leading to genetic instability, reduced repair capacity, photoaging, and carcinogenesis;

- Subsection 2.2 should include a reference to Figure 1, due to the involvement of sirtuins, PAR polymerases, and cADPRS synthases in NAM pathways;

- Table 3 - no references. What do the numbers (?) in parentheses mean?

- Line 378 - the acronym SASP genes is missing;

- Line 400 - the acronym "L values" is missing;

- Line 470 - Ferrell et al., 2024 - the reference does not meet the journal's requirements. Furthermore, this item is not listed in the References;

- Table 2 requires reformatting; it would be better to present it horizontally.

Author Response

Comment 1: Table 1 is very well-constructed, enriched with key findings, and concisely presents a wealth of information. However, confirmation of which of the presented effects are statistically significant is lacking.

Response: We thank the Reviewer for this positive comment. We have addressed this point by adding a dedicated column reporting the statistical significance of the results in all tables, in order to improve clarity and allow a more accurate interpretation of the reported findings.

 

Comment 2: Despite these mostly positive impressions, working with this amount of knowledge somewhat diminishes clarity and readability of presentation. First and foremost, describing some of the studies, conducted worldwide, in the text and presenting subsequent studies in Tables, which are not discussed in the text, creates an impression of data overload and a certain chaos. Tables should present data related to studies that are discussed in more detail in the text. Furthermore, in most cases described throughout the paper, the assessment of the significance of the results is omitted. The cognitive value and readability of the work would be greatly enhanced by the authors' selection of material and their focus on a more detailed discussion of the results, including statistical evaluation of even insignificant ones. After reading the current version of the work, drawing conclusions is extremely difficult.

Response: We thank the Reviewer for this insightful and constructive comment. We have revised Sections 4 and 5 to improve alignment between text and tables, streamline the narrative, and reduce redundancy. All studies are now consistently reported across text and tables, while detailed methodological and statistical information has been moved to the tables to improve readability. A new Table 4 has been added to summarize clinical and experimental evidence on topical nicotinamide in UV-induced immunosuppression and early photodamage, which was previously only described in the text.

 

Comment 3: Figure 2 requires correction – its content should imply (as described) that NAM supplementation maintains the NAD+ pool and, consequently, supports DNA repair processes, reduces inflammation, and oxidative stress. In the current version, this consequence is not apparent from the graphical portion of the figure. However, it does imply that NAM induces a decrease in NAD+ levels, leading to genetic instability, reduced repair capacity, photoaging, and carcinogenesis.

Response: We thank the Reviewer for this helpful comment. We agree that the previous version of Figure 2 could have been misleading regarding the role of NAM supplementation. Therefore, we revised the figure to clarify that NAM supplementation maintains the NAD⁺ pool, thereby supporting DNA repair capacity and reducing genomic instability, inflammation, and oxidative stress. In the revised figure, the red panel now shows decreased DNA repair capacity and increased genomic instability, inflammation, and oxidative stress, while the blue panel shows the opposite effects.

 

Comment 4: Subsection 2.2 should include a reference to Figure 1, due to the involvement of sirtuins, PAR polymerases, and cADPRS synthases in NAM pathways

Response: Accordingly, a reference to Figure 1 has been added in subsection 2.2

 

Comment 5: Table 3 - no references. What do the numbers (?) in parentheses mean?

Response: Table 3 has been revised and corrected, including the addition of the appropriate references and clarification/removal of the numbers previously reported in parentheses.

 

Comment 6: Line 378 - the acronym SASP genes is missing

Response: Acronym accordingly modified

 

Comment 7:  Line 400 - the acronym "L values" is missing

Response: The term “L* values” is no longer present in the revised version following manuscript editing.

 

Comment 8:  Line 470 - Ferrell et al., 2024 - the reference does not meet the journal's requirements. Furthermore, this item is not listed in the References

Response: The reference has been corrected according to the journal’s formatting requirements and properly included in the reference list.

 

 

Comment 9:  Table 2 requires reformatting; it would be better to present it horizontally.

Response: Table 2 has been reformatted and is now presented in a horizontal layout, as suggested.

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

N/A

Author Response

Dear Reviewer,

Thanks for your feedback. 

Reviewer 3 Report

Comments and Suggestions for Authors

 

Review No.4294290

The authors made all the corrections suggested by the reviewer.

The idea of presentation the general results of the study and including detailed information in the Tables was very good. From a substantive perspective, the work is very valuable and contributes a lot.

The problem with the work is mostly in editorial aspect, which the reviewer leaves to the authors to resolve. First of all, the reviewer refers to other works that publish large tables in horizontal orientation (it means: horizontal page orientation).

All Tables included in the revised work are incomplete (please note the last lines).

Regarding the numerical values illustrating statistical significance or its absence, this information is also not provided properly. These should be supplemented where possible, in accordance with the literature source (e.g., provide the p-value), or, if the source does not provide such data, write "no data."

Detailed editorial remarks:

• Table 1 - the previous table layout was more readable - to be considered.
• Line 365 - please correct as follows: [88][[6].
• Line 386 - please correct as follows: "(...) pigmentation regulation. mainly through (...)".
• Lines 374 and 385 - missing dots at the ends of the sentences.
• Line 395 - the reference [105] should be moved to the end of the sentence.

 

Author Response

Dear Reviewer, 

Comments: 

The authors made all the corrections suggested by the reviewer. The idea of presentation the general results of the study and including detailed information in the Tables was very good. From a substantive perspective, the work is very valuable and contributes a lot. The problem with the work is mostly in editorial aspect, which the reviewer leaves to the authors to resolve. First of all, the reviewer refers to other works that publish large tables in horizontal orientation (it means: horizontal page orientation). All Tables included in the revised work are incomplete (please note the last lines). Regarding the numerical values illustrating statistical significance or its absence, this information is also not provided properly. These should be supplemented where possible, in accordance with the literature source (e.g., provide the p-value), or, if the source does not provide such data, write "no data." Detailed editorial remarks:

• Table 1 - the previous table layout was more readable - to be considered.
• Line 365 - please correct as follows: [88][[6].
• Line 386 - please correct as follows: "(...) pigmentation regulation. mainly through (...)".
• Lines 374 and 385 - missing dots at the ends of the sentences.
• Line 395 - the reference [105] should be moved to the end of the sentence.

Response

We thank the Reviewer for this comment. The requested editorial revisions have been performed, and the statistical significance values are presented consistently within the tables.

Regarding the table layout, we respectfully defer to the Editor’s preference on the most appropriate format. Indeed, this specific suggestion appears to contrast with the feedback provided by another Reviewer, who requested that the tables be presented in a horizontal format. For the time being, we have therefore maintained the horizontal layout. However, we remain fully available to revise the tables again according to the Editor’s final guidance.