Histone Deacetylases in Neurodegenerative Diseases and Their Potential Role as Therapeutic Targets: Shedding Light on Astrocytes

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

1. The manuscript is well-written and provides a clear and comprehensive overview of HDACs and their potential as therapeutic targets in neurodegenerative diseases. The focus on astrocytes, which brings a fresh and relevant viewpoint to the area, really pleased me. However, few issues need to be addressed before it can be accepted for publication.

 

2. With its emphasis on the unmet need for multi-target therapy in Alzheimer's and related illnesses, the introduction skillfully sets the scene for the review. It would be better if the authors could briefly explain how HDAC research ties into more comprehensive epigenetic therapy techniques; it might be even more compelling. Adding a relevant citation related to HDAC research would even make it stronger. https://doi.org/10.3390/ph17111536

 

3. The section on HDAC classification and structural features is very informative, but at times, the level of detail may overwhelm a general readership. Consider condensing technical aspects or providing a summarising figure/table for clarity.

 

4. particularly neurodegenerative diseases (NDDs), has risen dramatically in recent decades. Among these, Alzheimer’s disease (AD) stands out as the most common and devastating form, representing a major public health concern …Check for consistency in abbreviation usage.

 

5. A future perspective section is missing, along with the Limitation section. It might benefit from a brief discussion of potential limitations, such as off-target effects, toxicity, and blood–brain barrier penetration challenges. Also, adding a short perspective on how precision medicine or omics approaches could guide HDACi development.

 

6. The authors should add a schematic figure summarizing the pharmacophore elements (ZBG, linker, cap group) could help readers unfamiliar with medicinal chemistry follow the discussion more easily.
7. The manuscript's strength is the part that focuses on astrocytic heterogeneity, which emphasizes how our knowledge of glial biology has advanced beyond the antiquated neuron-centric perspective.
8. The authors must include a summary table of HDAC inhibitors in clinical development for NDDs (phases, outcomes, sponsors)

Author Response

Comment 1: The manuscript is well-written and provides a clear and comprehensive overview of HDACs and their potential as therapeutic targets in neurodegenerative diseases. The focus on astrocytes, which brings a fresh and relevant viewpoint to the area, really pleased me. However, few issues need to be addressed before it can be accepted for publication.

Response: We sincerely thank you for your positive evaluation of our manuscript and for highlighting its clarity, comprehensive coverage of HDACs, and the novelty of focusing on astrocytes. We are very pleased that this perspective was appreciated.

Comment 2: With its emphasis on the unmet need for multi-target therapy in Alzheimer's and related illnesses, the introduction skillfully sets the scene for the review. It would be better if the authors could briefly explain how HDAC research ties into more comprehensive epigenetic therapy techniques; it might be even more compelling. Adding a relevant citation related to HDAC research would even make it stronger. https://doi.org/10.3390/ph17111536

Response: We thank the reviewer for this insightful suggestion. In the revised version of the Introduction, we expanded the section on epigenetic regulation to better contextualize HDAC research within the broader scope of epigenetic-based therapeutic strategies. We now emphasize how HDAC modulation represents a key component of integrated approaches aiming to restore balanced gene expression in neurodegenerative diseases. In addition, we incorporated the recommended citation to strengthen the discussion and provide a more comprehensive background.

Comment 3: The section on HDAC classification and structural features is very informative, but at times, the level of detail may overwhelm a general readership. Consider condensing technical aspects or providing a summarising figure/table for clarity.

We appreciate this constructive suggestion. To improve accessibility for a broader readership, we added a summary table (Table 1) that highlights the classification, cofactors, localization, and representative functions of each HDAC class. We believe this addition improves the clarity of the section.

Comment 4: Particularly neurodegenerative diseases (NDDs), has risen dramatically in recent decades. Among these, Alzheimer’s disease (AD) stands out as the most common and devastating form, representing a major public health concern …Check for consistency in abbreviation usage.

Response: We appreciate the reviewer’s observation. We carefully revised the manuscript to ensure consistency in the use of abbreviations.

Comment 5: A future perspective section is missing, along with the Limitation section. It might benefit from a brief discussion of potential limitations, such as off-target effects, toxicity, and blood–brain barrier penetration challenges. Also, adding a short perspective on how precision medicine or omics approaches could guide HDACi development.

Response: We thank the reviewer for this valuable suggestion. In the revised manuscript, we have consolidated the concluding remarks, limitations, and future perspectives into a single, coherent section titled Concluding Remarks and Future Perspectives.

In this section, we now discuss the key limitations of HDAC inhibitors, including the challenge of achieving isoform selectivity within the HDAC family, the intrinsic toxicity associated with hydroxamic acid derivatives due to hydroxylamine release, and the difficulties in achieving effective blood–brain barrier penetration.

Furthermore, the section highlights future directions for HDACi development. We emphasize the potential of omics-based and precision medicine approaches to identify patient- and cell-type-specific HDAC signatures, guide selective targeting, and predict treatment response. The need for novel chemical scaffolds beyond hydroxamic acids—such as benzamides, thiols, cyclic peptides, and other zinc-binding groups—is also discussed, to improve selectivity, safety, and pharmacokinetic properties. Finally, we outline the rational design of multi-target-directed HDAC inhibitors optimized for brain penetrance, astrocyte bioavailability, and complementary mechanisms such as autophagy enhancement, antioxidant support, and anti-inflammatory signaling.

We believe that these additions address the reviewer’s comments by providing a more comprehensive discussion of both current limitations and future therapeutic strategies for HDAC inhibitors in neurodegenerative diseases.

Comment 6: The authors should add a schematic figure summarizing the pharmacophore elements (ZBG, linker, cap group) could help readers unfamiliar with medicinal chemistry follow the discussion more easily.

Response: We thank the reviewer for this helpful suggestion. Figure 1, which already depicts the general pharmacophore elements of HDAC inhibitors, has been carefully revised and redrawn to enhance clarity and didactic value. The updated figure now more clearly highlights the zinc-binding group (ZBG), the linker, and the cap group, making it easier for readers, including those less familiar with medicinal chemistry, to follow the discussion.

Comment 7: The manuscript's strength is the part that focuses on astrocytic heterogeneity, which emphasizes how our knowledge of glial biology has advanced beyond the antiquated neuron-centric perspective.

Response: We sincerely thank the reviewer for highlighting this aspect of our manuscript. We fully agree that astrocytic heterogeneity is a key feature in understanding neurodegenerative disease pathophysiology and therapeutic response. In the revised manuscript, we have preserved and further clarified the discussion on astrocyte diversity and their role in disease progression and response to HDAC inhibitors, emphasizing the shift from neuron-centric to glia-inclusive perspectives in drug development.

Comment 8: The authors must include a summary table of HDAC inhibitors in clinical development for NDDs (phases, outcomes, sponsors)

Response: We thank the reviewer for the valuable suggestion. In response, we have included a new summary table (Table 2) that compiles clinical trials investigating various HDAC inhibitors for the treatment of neurodegenerative diseases, detailing the compounds, targeted HDAC isoforms, and trial phases. This table presents information on the compound name, clinical trial phase, study outcomes, and sponsoring institutions. We believe that this addition offers readers a clear and concise overview of the translational and clinical progress in HDAC inhibitor research, complementing the preclinical discussions presented in the manuscript.

Reviewer 2 Report

Comments and Suggestions for Authors

Manuscript named Histone Deacetylases in Neurodegenerative Diseases and its Potential Role as Therapeutic Targets: Shedding Light on Astrocytes is very comprehensive, analytical and systematic review of HDACi targeting astrocytes in therapy of NDD. 

Author Response

Comment: Manuscript named Histone Deacetylases in Neurodegenerative Diseases and its Potential Role as Therapeutic Targets: Shedding Light on Astrocytes is very comprehensive, analytical and systematic review of HDACi targeting astrocytes in therapy of NDD. 

Response: We sincerely thank Reviewer 2 for the positive and encouraging feedback. We are glad that the comprehensive, analytical, and systematic approach of our review, particularly regarding the role of HDAC inhibitors in astrocyte-targeted therapy for neurodegenerative diseases, is appreciated. The reviewer’s comments reinforce the relevance of highlighting glial biology alongside neuron-focused perspectives, which we believe is crucial for advancing multi-target therapeutic strategies.

 

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript “Histone Deacetylases in Neurodegenerative Diseases and its Potential Role as Therapeutic Targets: Shedding Light on Astrocytes” is excellently written by the authors. The manuscript gives an excellent overview of HDACs biology, pharmacophoric features of inhibitors, therapeutic implications, and the underexplored role of astrocytes. Citations include very recent studies (2023–2024), making the review current. The transition from neuron-centered views to astrocyte-focused therapeutic strategies is logical and well supported. Sections flow from general background (HDAC biology) to specific therapeutic applications and astrocytic roles, then into conclusions.

There are several grammatical errors that need to be addressed before this manuscript can be accepted.

• In the title, change "its" to "their"; it should read as "Histone Deacetylases in Neurodegenerative Diseases and Their Potential Role as Therapeutic Targets: Shedding Light on Astrocytes".
• There are a few minor grammatical errors, for instance, on page 4, line 9: "was also showed its relationship" should be corrected to "has also shown its relationship"; on page 14, paragraph 7, the last line: "rescuing Aβ clearance and mitigating astrocytic dysfunction" should be revised to "rescuing Aβ clearance and mitigate astrocytic dysfunction".
• Some sentences are excessively long, which affects clarity. It would be beneficial to break them up for better readability.
• Consistency in terminology is important. The term "HDACi" is sometimes used, while at other times "HDAC inhibitors" is used; it is advisable to choose one term and use it consistently throughout.
• Ensure consistent capitalization for terms such as astrocyte-reactive states and neurodegenerative diseases (NDDs).
• Figures are mentioned but not adequately explained in the text. Providing more context about what each figure illustrates would assist readers who are not familiar with structural biology.
• Sections 2–3 (structural biology, pharmacophores) are very detailed, whereas the sections discussing clinical progress and limitations are shorter. Expanding on the challenges of clinical trials (bioavailability, brain penetration, toxicity) would create a better balance.
• Make sure all abbreviations are defined upon their first use (e.g., PAPs, APDAs, DAAs).
• Some ideas (astrocyte heterogeneity, multi-target inhibitors) are repeated across various sections. These could be consolidated to enhance conciseness.

Finally, revise the title and abstract to ensure grammatical accuracy and enhance their impact. Edit lengthy sentences for better conciseness and clarity. Standardize the terminology between HDACi and HDAC inhibitors. Broaden the discussion on clinical translation challenges, including toxicity, pharmacokinetics, and blood-brain barrier penetration. Enhance figure integration by providing a brief summary of what each figure contributes to the argument. Eliminate placeholder editorial notes and verify the formatting of references. This review is robust and well-structured, with a solid scientific foundation. With some refinement in language, consistency in terminology, and a slightly more detailed clinical discussion, it will be well-prepared for publication.

Author Response

Comments: The manuscript “Histone Deacetylases in Neurodegenerative Diseases and its Potential Role as Therapeutic Targets: Shedding Light on Astrocytes” is excellently written by the authors. The manuscript gives an excellent overview of HDACs biology, pharmacophoric features of inhibitors, therapeutic implications, and the underexplored role of astrocytes. Citations include very recent studies (2023–2024), making the review current. The transition from neuron-centered views to astrocyte-focused therapeutic strategies is logical and well supported. Sections flow from general background (HDAC biology) to specific therapeutic applications and astrocytic roles, then into conclusions.

There are several grammatical errors that need to be addressed before this manuscript can be accepted.

• In the title, change "its" to "their"; it should read as "Histone Deacetylases in Neurodegenerative Diseases and Their Potential Role as Therapeutic Targets: Shedding Light on Astrocytes".
• There are a few minor grammatical errors, for instance, on page 4, line 9: "was also showed its relationship" should be corrected to "has also shown its relationship"; on page 14, paragraph 7, the last line: "rescuing Aβ clearance and mitigating astrocytic dysfunction" should be revised to "rescuing Aβ clearance and mitigate astrocytic dysfunction".
• Some sentences are excessively long, which affects clarity. It would be beneficial to break them up for better readability.
• Consistency in terminology is important. The term "HDACi" is sometimes used, while at other times "HDAC inhibitors" is used; it is advisable to choose one term and use it consistently throughout.
• Ensure consistent capitalization for terms such as astrocyte-reactive states and neurodegenerative diseases (NDDs).
• Figures are mentioned but not adequately explained in the text. Providing more context about what each figure illustrates would assist readers who are not familiar with structural biology.
• Sections 2–3 (structural biology, pharmacophores) are very detailed, whereas the sections discussing clinical progress and limitations are shorter. Expanding on the challenges of clinical trials (bioavailability, brain penetration, toxicity) would create a better balance.
• Make sure all abbreviations are defined upon their first use (e.g., PAPs, APDAs, DAAs).
• Some ideas (astrocyte heterogeneity, multi-target inhibitors) are repeated across various sections. These could be consolidated to enhance conciseness.

Finally, revise the title and abstract to ensure grammatical accuracy and enhance their impact. Edit lengthy sentences for better conciseness and clarity. Standardize the terminology between HDACi and HDAC inhibitors. Broaden the discussion on clinical translation challenges, including toxicity, pharmacokinetics, and blood-brain barrier penetration. Enhance figure integration by providing a brief summary of what each figure contributes to the argument. Eliminate placeholder editorial notes and verify the formatting of references. This review is robust and well-structured, with a solid scientific foundation. With some refinement in language, consistency in terminology, and a slightly more detailed clinical discussion, it will be well-prepared for publication.

Response: We sincerely thank the reviewer for the thorough and constructive assessment of our manuscript. In response, we have carefully revised the entire text to address all the points raised, including correction of grammatical errors, improved sentence clarity and conciseness, standardization of terminology (HDACi/HDAC inhibitors), consistent abbreviation usage, refinement of the title and abstract, and enhanced figure integration with explanatory context. Additionally, we expanded the discussion on clinical translation challenges (bioavailability, brain penetration, and toxicity) and consolidated overlapping ideas to improve conciseness. We believe these revisions have significantly strengthened the manuscript, and we are grateful for the reviewer’s valuable input, which has guided us in improving both the scientific rigor and readability of the work.

Reviewer 4 Report

Comments and Suggestions for Authors

The manuscript presents a comprehensive and timely review of histone deacetylases (HDACs) and HDAC inhibitors (HDACi) in the context of neurodegenerative diseases, with a special focus on astrocytes. The topic is highly relevant given the emerging recognition of astrocyte heterogeneity and the increasing interest in glia-focused therapeutic strategies. The paper is well-organized, thorough in scope, and integrates both mechanistic insights and therapeutic implications.

Major Strengths

1. The focus on astrocytes as therapeutic targets, rather than only neurons, fills an important gap in the field. Clear discussion of astrocytic phenotypes (A1/A2, DAAs, APDAs, LARAs) and their link with HDAC signaling is valuable.
2. Comprehensive coverage of HDAC classification, structural biology, pharmacophoric features of HDAC inhibitors, and clinical trials.
3. Figures illustrating binding pockets, pharmacophore models, and isoform selectivity (e.g., HDAC4 vs. HDAC8, HDAC6 inhibitors) help the reader appreciate drug design principles.
4. Linking preclinical findings to ongoing or completed clinical trials strengthens the translational relevance.

Major Concerns

1. At ~28 pages, the manuscript is dense and at times repetitive (e.g., multiple mentions of HDAC3’s role in astrocyte reactivity). The review could benefit from streamlining.
2. While the astrocyte focus is highlighted in the title, the majority of the review still centers on classical neuronal HDAC functions. Consider tightening background neuronal content to give more weight to astrocytic insights.
3. A brief table summarizing approved HDACi, targets, and clinical indications would improve readability.
4. Much of the text is descriptive. A more critical discussion of limitations and controversies would strengthen the paper, including:

Reasons why many HDACi clinical trials for NDDs have not progressed successfully.

Potential toxicity and off-target issues.

Challenges in achieving selective targeting astrocytes in vivo.

Author Response

Comments: The manuscript presents a comprehensive and timely review of histone deacetylases (HDACs) and HDAC inhibitors (HDACi) in the context of neurodegenerative diseases, with a special focus on astrocytes. The topic is highly relevant given the emerging recognition of astrocyte heterogeneity and the increasing interest in glia-focused therapeutic strategies. The paper is well-organized, thorough in scope, and integrates both mechanistic insights and therapeutic implications.

Major Strengths

1. The focus on astrocytes as therapeutic targets, rather than only neurons, fills an important gap in the field. Clear discussion of astrocytic phenotypes (A1/A2, DAAs, APDAs, LARAs) and their link with HDAC signaling is valuable.
2. Comprehensive coverage of HDAC classification, structural biology, pharmacophoric features of HDAC inhibitors, and clinical trials.
3. Figures illustrating binding pockets, pharmacophore models, and isoform selectivity (e.g., HDAC4 vs. HDAC8, HDAC6 inhibitors) help the reader appreciate drug design principles.
4. Linking preclinical findings to ongoing or completed clinical trials strengthens the translational relevance.

Major Concerns

1. At ~28 pages, the manuscript is dense and at times repetitive (e.g., multiple mentions of HDAC3’s role in astrocyte reactivity). The review could benefit from streamlining.
2. While the astrocyte focus is highlighted in the title, the majority of the review still centers on classical neuronal HDAC functions. Consider tightening background neuronal content to give more weight to astrocytic insights.
3. A brief table summarizing approved HDACi, targets, and clinical indications would improve readability.
4. Much of the text is descriptive. A more critical discussion of limitations and controversies would strengthen the paper, including:

Reasons why many HDACi clinical trials for NDDs have not progressed successfully.

Potential toxicity and off-target issues.

Challenges in achieving selective targeting astrocytes in vivo.

Response: We sincerely thank the reviewer for the careful assessment and constructive major comments, which have helped us substantially improve the manuscript. In response, we have made the following revisions:

1. The manuscript has been carefully revised to reduce redundancy and improve readability. Repetitive passages (e.g., regarding HDAC3’s role in astrocyte reactivity) have been consolidated, resulting in a more concise presentation.
2. We thank the reviewer for this observation. The manuscript has been carefully revised to reduce redundancy and improve readability. Repetitive passages (e.g., regarding HDAC3’s role in astrocyte reactivity) have been consolidated, resulting in a more concise presentation.
3. We appreciate the reviewer’s suggestion. In response, Figure 1 has been revised to incorporate the requested information, now providing a clearer summary of approved HDAC inhibitors, their targets, and clinical indications, thereby improving readability and accessibility for the readers.

4. We have significantly strengthened the “Concluding Remarks and Future Perspectives” section by critically addressing key limitations and controversies, including: the main reasons why clinical trials of HDAC inhibitors for neurodegenerative diseases have shown limited success to date; toxicity concerns, with particular emphasis on hydroxamic acid derivatives and their release of hydroxylamine; challenges related to isoform selectivity within the HDAC family; difficulties in achieving efficient brain penetration and selective targeting of astrocytes in vivo.

We believe that these revisions not only address the reviewer’s concerns but also enhance the balance, critical depth, and overall impact of the manuscript.