Current and Developing Therapeutics for Dry Eye Disease: Targeting Ion Channels

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This manuscript presents a comprehensive and well-structured review of the role of ion channels—specifically TRP channels, voltage-gated sodium (Nav) channels, and purinergic P2X receptors—in the pathophysiology of dry eye disease (DED) and neuropathic ocular pain. The topic is relevant, particularly given the increasing recognition of neuropathic mechanisms contributing to ocular surface pain in patients who remain symptomatic despite conventional lubrication and anti-inflammatory therapies.

The review summarizes the anatomical distribution, molecular function, and environmental responsiveness (heat, cold, hyperosmolarity, injury) of the major ion channel families involved in ocular surface homeostasis and nociception. The integration of sensory neuroscience with clinical DED management is particularly valuable. Importantly, the manuscript provides actionable clinical insights by linking ion channel activity with existing therapies (artificial tears, anti-inflammatory agents, systemic neuromodulators) and introducing emerging treatments targeting sensory transduction pathways.

The illustrations are clear and educational, facilitating understanding of complex molecular mechanisms and neural pathways. The figures meaningfully enhance the didactic quality of the manuscript and make it accessible to clinicians who may not have a strong background in molecular neurobiology.

However, a substantial portion of the manuscript reiterates data that have already been comprehensively summarized in prior literature, including the review by Ashok et al. (Ion channels in dry eye disease. Indian J Ophthalmol. 2023;71:1215–1226). Although the authors appropriately cite this source, the conceptual structure, channel categorization, and mechanistic descriptions overlap considerably with previously published material. The current manuscript would benefit from a clearer delineation of what is novel—whether in updated data, expanded mechanistic insight, refined clinical correlations, or therapeutic advancements beyond what has already been reviewed.

To strengthen the contribution, the authors could:

1. Provide deeper analysis of recently emerging therapeutic agents targeting ion channels.
2. Emphasize new experimental or clinical findings published after 2023.

In summary, this is a well-written, clinically relevant review with strong educational value and practical management implications. However, its novelty is somewhat limited due to significant overlap with previously published comprehensive reviews on the same topic. With further emphasis on recent advances and clearer differentiation from existing literature, the manuscript could make a stronger independent contribution to the field.

Author Response

Please see the attachment. 

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Dear Authors,

Thank you for the opportunity to review your interesting and timely manuscript on current and developing therapeutics for Dry Eye Disease, with particular emphasis on targeting ion channels. The topic is highly relevant to ongoing clinical practice and emerging research in ocular surface disease, and the manuscript brings together a number of valuable insights and references that will be useful to readers in the field.

Overall, the review addresses an important and evolving area of therapeutic development. The discussion of ion channels as potential therapeutic targets is especially noteworthy, as this area is gaining increasing attention in both basic and translational research related to Dry Eye Disease.

That said, I believe the manuscript would benefit from some minor revisions to further strengthen its presentation and clarity. In particular, improvements in the overall structure and organization of certain sections could enhance the logical flow and readability of the paper. In addition, some of the key figures may need refinement to better illustrate the concepts discussed and to improve their clarity for readers.

I also noticed that in a few places the drug names appear to be slightly inconsistent or potentially misleading. I would recommend carefully reviewing the terminology and nomenclature to ensure accuracy and consistency throughout the manuscript.

For your convenience, I have included my comments and suggestions directly in the attached revision file, where they are highlighted in yellow. I hope these remarks will be helpful as you revise and further strengthen the manuscript.

Thank you again for your contribution to this important area of research. I appreciate the opportunity to review your work and look forward to seeing the revised version.

Best regards

Comments for author File: Comments.pdf

Author Response

Please see the attachment. 

Author Response File: Author Response.pdf