Peculiar Cat with Many Lives: PUMA in Viral Infections

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This draft clearly explains how PUMA, a key cell death protein, acts as a double-edged sword in fighting viruses. It connects detailed biology to real diseases and organizes complex information in a logical, readable way. The review effectively highlights PUMA's potential as both a treatment target and a disease marker.

1- Explain when and why each protein activates PUMA. In the Molecular Biology section, briefly state the main situation (like DNA damage or stress) that triggers p53, FOXO3a, E2F1, or p73 to turn on the PUMA gene. 

2- Group how viruses control PUMA into clear categories. After discussing each virus, add a short summary or a table that lists the common tricks viruses use, such as "blocking PUMA gene reading," "trapping the PUMA protein," or "forcing too much PUMA production." 

3- Discuss the difficulties in creating PUMA-based treatments. In the Therapeutic Target section, add a note about potential problems.

4- Connect the dots between virus mechanisms and potential treatments. In the Conclusion, clearly state how knowing a virus's specific trick (from Section 3) points to the best treatment approach (from Section 4). 

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

The submitted narrative review introduces PUMA as a BH3-only “apoptotic hub” and surveys how diverse human viruses (EBV, HSV-1, HBV, HIV-1, MeV, IAV, DENV, ZIKV) manipulate or exploit PUMA-driven pathways. The topic is timely and potentially impactful; however, the manuscript’s structure, depth balance, and translational framing require improvement.

Major points:

-Novelty: The Introduction promises “a comprehensive overview” of PUMA in virology PUMA and viral infection yet does not explain how this review extends or updates earlier PUMA/apoptosis reviews (e.g., 2023–24 literature). Specify the unique angel/perspectives of this review in the final paragraph of the Introduction.

- Search strategy & inclusion criteria: No methods section details how the literature was retrieved, filtered, or prioritized. Provide database(s) queried, time window, key terms, and selection criteria to enhance reproducibility.

- Reduce redundancy: Sections 1–2 devote have extensive canonical apoptosis mechanisms are partially repeated in the Abstract/Introduction. Condense background to focus on PUMA-specific aspects.

-Therapeutic translation: The review mentions “therapeutic implications” but lacks detail on current drug development. Add a subsection summarising (i) PUMA mimetics, (ii) viral BH3-antagonist inhibitors, and (iii) ongoing clinical/IND-stage trials (registry numbers where available).

- Figures: Figure 1 is visually appealing but crowded; font size is unreadable when printed. Provide high-resolution panels or split into two figures (virus-specific vs signaling schematic). Add a PUMA-centered interaction map summarizing pro- vs anti-apoptotic viral factors.

- Conclusions -lack of future perspectives
Research gaps are not highlighted, but rather restated in the review content

Minor:

-Define Abbreviations at first mention, check carefully.

Author Response

Please see the attachment.

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for your detailed responses and revisions.

Reviewer 2 Report

Comments and Suggestions for Authors

The revised manuscript is well prepared and meets the quality required for publication. Congratulations.