Review Reports

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Over the last few decades, hyperuricemia (HUA), characterized by elevated serum urate levels, has evolved from a disease of gouty arthritis to a recognized risk factor for cardiometabolic and kidney disease. In this review, the emphasis shifts from clinical management to mechanistic understanding of hyperuricemia interventions. Despite the relevance/importance of the topic, this review needs to be revised for the following reasons. In the review, hyperuricemia should be framed as a multifactorial disorder, followed by interventions systematically examined through the lens of molecular mechanisms rather than just outcomes. While integrating lifestyle and emerging therapies, interventions should be classified according to their pharmacological targets or pathways - urine production, excretion, inflammation. It is apparent from the title of the review that there is a contrast between the "from...to..." in the title. Management should begin with broad strategies and then drill down to specific mechanisms such as the inhibition of XOR, the modulation of URAT1, or the disruption of NLRP3 inflammasome. The response should highlight the key mechanistic insights behind each intervention class with a summary table. This review will benefit from substantial revision. Specific commentary below - some sections and key contents for each section are recommended/listed/provided.

1. The Multidimensional Management Framework - Traditional management is multidimensional, involving lifestyle modifications and pharmacotherapy.

The foundation of this intervention consists of reducing purine-rich foods (e.g., red meat, seafood), high-fructose beverages, and alcohol (particularly beer). It emphasizes weight loss, a balanced diet (e.g., DASH diet), increased water intake, and consumption of low-fat dairy products. While effective, adherence is often difficult, and efficacy is limited in patients with moderate-to-severe HUA.

Pharmacological Therapy: First-Line Urate-Lowering Therapy (ULT): Xanthine Oxidase Inhibitors (XOIs). Uricosurics, Uricase Therapies and Anti-Inflammatory Prophylaxis. Low-dose colchicine or NSAIDs are used during initial ULT to prevent gout flares driven by the NLRP3 inflammasome activation upon mobilization of urate crystals.

2. Molecular mechanistic Insights – XOIx, the renal transportome (multiple urate transporters (e.g., URAT1, GLUT9/SLC2A9, ABCG2) has refined the action of uricosurics), inflammation as a core pathway (such as Nlrp3 inflammasome) and gut as a novel frontier (Modulation of the gut microbiota (e.g., Lactobacillus* strains expressing uricase) and use of uricosuric probiotics or selective gut URAT1 inhibitors (e.g., topiroxostat has some gut activity) are emerging areas of research, offering a non-renal excretion pathway)

Author Response

Point-by-Point Response to Reviewers’ Comments

Dear editor and reviewers,

We sincerely thank you and the reviewers for the constructive comments on our manuscript. We have carefully considered all suggestions and thoroughly revised the manuscript accordingly. The changes have significantly improved the quality and clarity of our work. Revisions are highlighted in red in the revised manuscript. Below, we provide a point-by-point response to the reviewers' comments, detailing the revisions made.

Response to Reviewer #1

General comments

In this review, the emphasis shifts from clinical management to mechanistic understanding of hyperuricemia interventions. Despite the relevance/importance of the topic, this review needs to be revised for the following reasons. In the review, hyperuricemia should be framed as a multifactorial disorder, followed by interventions systematically examined through the lens of molecular mechanisms rather than just outcomes. While integrating lifestyle and emerging therapies, interventions should be classified according to their pharmacological targets or pathways - urine production, excretion, inflammation. It is apparent from the title of the review that there is a contrast between the "from...to..." in the title. Management should begin with broad strategies and then drill down to specific mechanisms such as the inhibition of XOR, the modulation of URAT1, or the disruption of NLRP3 inflammasome. The response should highlight the key mechanistic insights behind each intervention class with a summary table. This review will benefit from substantial revision.

Response:

Thank you for this valuable suggestion. We fully agree that framing hyperuricemia as a multifactorial disorder and analyzing interventions through specific molecular targets provides deeper scientific value. We have made the following revisions as you suggested:

Descriptions of these specific mechanisms including the inhibition of XOR, the modulation of URAT1, and the disruption of NLRP3 inflammasome have been added following the relevant intervention strategies to make a smooth shift from outcomes to mechanisms. (lines 190-194, lines 624-627)

We have added a new summary table (now Table 2 in the revised manuscript) to highlight the key mechanistic insights underlying each category of intervention modality and their evidence levels. (lines 633)

Specific concerns

SC#1: The Multidimensional Management Framework - Traditional management is multidimensional, involving lifestyle modifications and pharmacotherapy. The foundation of this intervention consists of reducing purine-rich foods (e.g., red meat, seafood), high-fructose beverages, and alcohol (particularly beer). It emphasizes weight loss, a balanced diet (e.g., DASH diet), increased water intake, and consumption of low-fat dairy products. While effective, adherence is often difficult, and efficacy is limited in patients with moderate-to-severe HUA. Pharmacological Therapy: First-Line Urate-Lowering Therapy (ULT): Xanthine Oxidase Inhibitors (XOIs). Uricosurics, Uricase Therapies and Anti-Inflammatory Prophylaxis. Low-dose colchicine or NSAIDs are used during initial ULT to prevent gout flares driven by the NLRP3 inflammasome activation upon mobilization of urate crystals.

Response SC#1:

We sincerely thank you for this constructive comment that helps us better articulate the multidimensional management framework for HUA. We fully agree with the importance of presenting a comprehensive and systematic overview. 

We have significantly expanded and reorganized the description of the "Multidimensional Management Framework" in the Introduction section. This section now explicitly outlines the stepwise approach, starting with foundational lifestyle modifications (including dietary control, weight loss, and increased water intake as suggested), honestly discussing their challenges with adherence and limited efficacy in moderate-to-severe cases, which logically leads to the necessity of pharmacological therapy.(lines 52-58).

Additionally, we have incorporated the information about Xanthine Oxidase Inhibitors as first-line ULT, Uricosurics, Uricase therapies, and Anti-inflammatory prophylaxis with low-dose colchicine/NSAIDs into the revised framework, ensuring a complete representation of management strategies.(lines 424-426)

SC#2：Molecular mechanistic Insights – XOIx, the renal transportome (multiple urate transporters (e.g., URAT1, GLUT9/SLC2A9, ABCG2) has refined the action of uricosurics), inflammation as a core pathway (such as Nlrp3 inflammasome) and gut as a novel frontier (Modulation of the gut microbiota (e.g., Lactobacillus* strains expressing uricase) and use of uricosuric probiotics or selective gut URAT1 inhibitors (e.g., topiroxostat has some gut activity) are emerging areas of research, offering a non-renal excretion pathway)

Response SC#2:

We sincerely thank you for this insightful suggestion. We have incorporated these molecular mechanistic insights into the relevant sections to shift the manuscript's emphasis towards a deeper, mechanism-based understanding of HUA interventions. (e.g., lines 164-168, lines 190-194, lines 308-311)

 

 

Response to Reviewer #2

General comments:

Overall, this manuscript is a mechanistically rich review of therapeutics for hyperuricemia. It is well aligned with the aims and scope of the International Journal of Molecular Sciences. The strength of this review lies in its breadth and molecular and integrated perspectives. Furthermore, the methodology should be more transparent, preclinical and clinical evidence should better balance, and each section should be clearer.

Response:

We appreciate your positive feedback and valuable suggestions. We agree with this comment. Therefore，We have made the necessary revisions in the revised manuscript based on your comments.

Specific concerns

SC#1: The manuscript lacks a description of the review methodology used, such as the databases searched date limit or the inclusion/exclusion criteria. If this paper is considered a narrative review, a Methods section outlining the selection criteria could improve transparency.

Response SC#1:

Thank you for pointing this out. We agree with this comment. A brief description of the review methodology has been included in the revised manuscript. (lines 69-79)

SC#2: Some mechanistic beliefs have mainly been shown only in animal or in vitro studies, and have heterogeneous clinical support.The authors should clarify which findings are supported by clinical studies in humans and which are mainly based on preclinical data.

Response SC#2:

This is a vital point. We have meticulously gone through the text to qualify statements regarding the evidence base. We now explicitly state whether findings are supported by "clinical studies," "preclinical models," or are "hypothesized mechanisms." This is evident in Section 4.2 (Gut Microbiota) and Section 5 (Mechanisms).

SC#3: Some statements in the gut microbiota and customary Chinese medicine interventions sections insinuate clinical readiness, despite limited clinical evaluation.

Response SC#3:

Thanks for your suggestion. We have toned down statements, particularly in the gut microbiota and traditional Chinese medicine sections, to avoid overstating clinical readiness. Phrases like "shows promise" or "preclinical evidence suggests" are used (e.g., line 313, 317). In addition, we emphasized the challenges in clinical translation and future perspectives to explicitly address the gaps between mechanistic understanding and clinical application.(lines 321-322)

SC#4: With clinical translation and potential long-term effects in mind, further caution is warranted.

Response SC#4:

We agree with your point of view. We have emphasized this in the “Conclusion and Perspectives” section.(lines 647-651)

SC#5: Care must be exercised when summarizing overlapping studies, establishing no-effect safety thresholds, and determining recommendations specific to different populations.

Response SC#5:

We sincerely thank you for this critical comment regarding the need for caution in evidence synthesis and clinical recommendation. We fully agree with this point. In response, we have thoroughly revised the manuscript to ensure greater scientific rigor:

Summarizing overlapping studies: throughout the text, especially in sections discussing areas with conflicting evidence (e.g., Resistance Exercise interventions, lines 383，lines389-390), we now present a balanced view by citing studies with both positive and negative outcomes, and we discuss potential reasons for the discrepancies.

Establishing safety thresholds: we have replaced absolute statements about drug safety (e.g., "safe," ) with more precise language (e.g., "demonstrated a favorable safety profile in trials to date") (e.g., lines 353-354, lines 438-439) and have explicitly mentioned known limitations, such as the lack of long-term safety data for newer agents.(e.g., line 441-447)

Population-specific recommendations: we have added a dedicated paragraph in the “Conclusion and Perspectives” section to highlight the importance of tailoring management strategies to specific patient populations (e.g., CKD, elderly, pediatric), acknowledging the limitations of generalizing findings. (lines 652-661)

SC#6: Although a central theme of the manuscript, children and adolescents with HUA receive less focused discussion. Elaboration on this issue would strengthen the public health relevance of the review.

Response SC#6:

We appreciate your kind suggestion. We have enhanced the discussion on pediatric HUA in the relevant sections, highlighting its unique clinical entity and the distinct lack of robust evidence. (e.g., lines 652-661 )

SC#7: Use hyperuricemia (HUA) consistently throughout.

Response SC#7:

Thank you for pointing this out. We have thoroughly reviewed the entire manuscript to correct and standardize the relevant expressions. (e.g., lines 151, 635, 664)

SC#8: Some sections could include schematic summary figures or tables to reduce wordiness.

Response SC#8:

We appreciate the constructive feedback. In response, we have incorporated a summary table (now Table 2 in the revised manuscript) that outlines the key molecular targets for various HUA intervention modalities alongside their corresponding levels of evidence. Furthermore, the manuscript has been thoroughly streamlined to enhance clarity.

SC#9: Refine minor English language for fluency and readability, especially in longer mechanistic paragraphs.

Response SC#9:

We have carefully reviewed the entire manuscript and improved the English expression throughout the text.

SC#10: Define abbreviations when first used within the text, even if the glossary already defines them.

Response SC#10:

We appreciate your kind reminding. We have carefully reviewed the entire manuscript and revised the relevant sections accordingly.

 

Thank you once again for your guidance and support throughout this process. I look forward to hearing from you soon.

Sincerely,

Dr. Lijun Yin 

Assistant Professor

School of Sports, Shenzhen University

yinlijun@szu.edu.cn

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

Overall, this manuscript is a mechanistically rich review of therapeutics for hyperuricemia. It is well aligned with the aims and scope of the International Journal of Molecular Sciences. The strength of this review lies in its breadth and molecular and integrated perspectives. Furthermore, the methodology should be more transparent, preclinical and clinical evidence should better balance, and each section should be clearer.

Major:

1. The manuscript lacks a description of the review methodology used, such as the databases searched date limit or the inclusion/exclusion criteria. If this paper is considered a narrative review, a Methods section outlining the selection criteria could improve transparency.
2. Some mechanistic beliefs have mainly been shown only in animal or in vitro studies, and have heterogeneous clinical support.
3. The authors should clarify which findings are supported by clinical studies in humans and which are mainly based on preclinical data.
4. Some statements in the gut microbiota and customary Chinese medicine interventions sections insinuate clinical readiness, despite limited clinical evaluation.
5. With clinical translation and potential long-term effects in mind, further caution is warranted.
6. Care must be exercised when summarizing overlapping studies, establishing no-effect safety thresholds, and determining recommendations specific to different populations.
7. Although a central theme of the manuscript, children and adolescents with HUA receive less focused discussion. Elaboration on this issue would strengthen the public health relevance of the review.

Minor:

1. Use hyperuricemia (HUA) consistently throughout.
2. Some sections could include schematic summary figures or tables to reduce wordiness.
3. Refine minor English language for fluency and readability, especially in longer mechanistic paragraphs.
4. Define abbreviations when first used within the text, even if the glossary already defines them.

Author Response

Point-by-Point Response to Reviewers’ Comments

Dear editor and reviewers,

We sincerely thank you and the reviewers for the constructive comments on our manuscript. We have carefully considered all suggestions and thoroughly revised the manuscript accordingly. The changes have significantly improved the quality and clarity of our work. Revisions are highlighted in red in the revised manuscript. Below, we provide a point-by-point response to the reviewers' comments, detailing the revisions made.

Response to Reviewer #1

General comments

In this review, the emphasis shifts from clinical management to mechanistic understanding of hyperuricemia interventions. Despite the relevance/importance of the topic, this review needs to be revised for the following reasons. In the review, hyperuricemia should be framed as a multifactorial disorder, followed by interventions systematically examined through the lens of molecular mechanisms rather than just outcomes. While integrating lifestyle and emerging therapies, interventions should be classified according to their pharmacological targets or pathways - urine production, excretion, inflammation. It is apparent from the title of the review that there is a contrast between the "from...to..." in the title. Management should begin with broad strategies and then drill down to specific mechanisms such as the inhibition of XOR, the modulation of URAT1, or the disruption of NLRP3 inflammasome. The response should highlight the key mechanistic insights behind each intervention class with a summary table. This review will benefit from substantial revision.

Response:

Thank you for this valuable suggestion. We fully agree that framing hyperuricemia as a multifactorial disorder and analyzing interventions through specific molecular targets provides deeper scientific value. We have made the following revisions as you suggested:

Descriptions of these specific mechanisms including the inhibition of XOR, the modulation of URAT1, and the disruption of NLRP3 inflammasome have been added following the relevant intervention strategies to make a smooth shift from outcomes to mechanisms. (lines 190-194, lines 624-627)

We have added a new summary table (now Table 2 in the revised manuscript) to highlight the key mechanistic insights underlying each category of intervention modality and their evidence levels. (lines 633)

Specific concerns

SC#1: The Multidimensional Management Framework - Traditional management is multidimensional, involving lifestyle modifications and pharmacotherapy. The foundation of this intervention consists of reducing purine-rich foods (e.g., red meat, seafood), high-fructose beverages, and alcohol (particularly beer). It emphasizes weight loss, a balanced diet (e.g., DASH diet), increased water intake, and consumption of low-fat dairy products. While effective, adherence is often difficult, and efficacy is limited in patients with moderate-to-severe HUA. Pharmacological Therapy: First-Line Urate-Lowering Therapy (ULT): Xanthine Oxidase Inhibitors (XOIs). Uricosurics, Uricase Therapies and Anti-Inflammatory Prophylaxis. Low-dose colchicine or NSAIDs are used during initial ULT to prevent gout flares driven by the NLRP3 inflammasome activation upon mobilization of urate crystals.

Response SC#1:

We sincerely thank you for this constructive comment that helps us better articulate the multidimensional management framework for HUA. We fully agree with the importance of presenting a comprehensive and systematic overview. 

We have significantly expanded and reorganized the description of the "Multidimensional Management Framework" in the Introduction section. This section now explicitly outlines the stepwise approach, starting with foundational lifestyle modifications (including dietary control, weight loss, and increased water intake as suggested), honestly discussing their challenges with adherence and limited efficacy in moderate-to-severe cases, which logically leads to the necessity of pharmacological therapy.(lines 52-58).

Additionally, we have incorporated the information about Xanthine Oxidase Inhibitors as first-line ULT, Uricosurics, Uricase therapies, and Anti-inflammatory prophylaxis with low-dose colchicine/NSAIDs into the revised framework, ensuring a complete representation of management strategies.(lines 424-426)

SC#2：Molecular mechanistic Insights – XOIx, the renal transportome (multiple urate transporters (e.g., URAT1, GLUT9/SLC2A9, ABCG2) has refined the action of uricosurics), inflammation as a core pathway (such as Nlrp3 inflammasome) and gut as a novel frontier (Modulation of the gut microbiota (e.g., Lactobacillus* strains expressing uricase) and use of uricosuric probiotics or selective gut URAT1 inhibitors (e.g., topiroxostat has some gut activity) are emerging areas of research, offering a non-renal excretion pathway)

Response SC#2:

We sincerely thank you for this insightful suggestion. We have incorporated these molecular mechanistic insights into the relevant sections to shift the manuscript's emphasis towards a deeper, mechanism-based understanding of HUA interventions. (e.g., lines 164-168, lines 190-194, lines 308-311)

 

 

Response to Reviewer #2

General comments:

Overall, this manuscript is a mechanistically rich review of therapeutics for hyperuricemia. It is well aligned with the aims and scope of the International Journal of Molecular Sciences. The strength of this review lies in its breadth and molecular and integrated perspectives. Furthermore, the methodology should be more transparent, preclinical and clinical evidence should better balance, and each section should be clearer.

Response:

We appreciate your positive feedback and valuable suggestions. We agree with this comment. Therefore，We have made the necessary revisions in the revised manuscript based on your comments.

Specific concerns

SC#1: The manuscript lacks a description of the review methodology used, such as the databases searched date limit or the inclusion/exclusion criteria. If this paper is considered a narrative review, a Methods section outlining the selection criteria could improve transparency.

Response SC#1:

Thank you for pointing this out. We agree with this comment. A brief description of the review methodology has been included in the revised manuscript. (lines 69-79)

SC#2: Some mechanistic beliefs have mainly been shown only in animal or in vitro studies, and have heterogeneous clinical support.The authors should clarify which findings are supported by clinical studies in humans and which are mainly based on preclinical data.

Response SC#2:

This is a vital point. We have meticulously gone through the text to qualify statements regarding the evidence base. We now explicitly state whether findings are supported by "clinical studies," "preclinical models," or are "hypothesized mechanisms." This is evident in Section 4.2 (Gut Microbiota) and Section 5 (Mechanisms).

SC#3: Some statements in the gut microbiota and customary Chinese medicine interventions sections insinuate clinical readiness, despite limited clinical evaluation.

Response SC#3:

Thanks for your suggestion. We have toned down statements, particularly in the gut microbiota and traditional Chinese medicine sections, to avoid overstating clinical readiness. Phrases like "shows promise" or "preclinical evidence suggests" are used (e.g., line 313, 317). In addition, we emphasized the challenges in clinical translation and future perspectives to explicitly address the gaps between mechanistic understanding and clinical application.(lines 321-322)

SC#4: With clinical translation and potential long-term effects in mind, further caution is warranted.

Response SC#4:

We agree with your point of view. We have emphasized this in the “Conclusion and Perspectives” section.(lines 647-651)

SC#5: Care must be exercised when summarizing overlapping studies, establishing no-effect safety thresholds, and determining recommendations specific to different populations.

Response SC#5:

We sincerely thank you for this critical comment regarding the need for caution in evidence synthesis and clinical recommendation. We fully agree with this point. In response, we have thoroughly revised the manuscript to ensure greater scientific rigor:

Summarizing overlapping studies: throughout the text, especially in sections discussing areas with conflicting evidence (e.g., Resistance Exercise interventions, lines 383，lines389-390), we now present a balanced view by citing studies with both positive and negative outcomes, and we discuss potential reasons for the discrepancies.

Establishing safety thresholds: we have replaced absolute statements about drug safety (e.g., "safe," ) with more precise language (e.g., "demonstrated a favorable safety profile in trials to date") (e.g., lines 353-354, lines 438-439) and have explicitly mentioned known limitations, such as the lack of long-term safety data for newer agents.(e.g., line 441-447)

Population-specific recommendations: we have added a dedicated paragraph in the “Conclusion and Perspectives” section to highlight the importance of tailoring management strategies to specific patient populations (e.g., CKD, elderly, pediatric), acknowledging the limitations of generalizing findings. (lines 652-661)

SC#6: Although a central theme of the manuscript, children and adolescents with HUA receive less focused discussion. Elaboration on this issue would strengthen the public health relevance of the review.

Response SC#6:

We appreciate your kind suggestion. We have enhanced the discussion on pediatric HUA in the relevant sections, highlighting its unique clinical entity and the distinct lack of robust evidence. (e.g., lines 652-661 )

SC#7: Use hyperuricemia (HUA) consistently throughout.

Response SC#7:

Thank you for pointing this out. We have thoroughly reviewed the entire manuscript to correct and standardize the relevant expressions. (e.g., lines 151, 635, 664)

SC#8: Some sections could include schematic summary figures or tables to reduce wordiness.

Response SC#8:

We appreciate the constructive feedback. In response, we have incorporated a summary table (now Table 2 in the revised manuscript) that outlines the key molecular targets for various HUA intervention modalities alongside their corresponding levels of evidence. Furthermore, the manuscript has been thoroughly streamlined to enhance clarity.

SC#9: Refine minor English language for fluency and readability, especially in longer mechanistic paragraphs.

Response SC#9:

We have carefully reviewed the entire manuscript and improved the English expression throughout the text.

SC#10: Define abbreviations when first used within the text, even if the glossary already defines them.

Response SC#10:

We appreciate your kind reminding. We have carefully reviewed the entire manuscript and revised the relevant sections accordingly.

 

Thank you once again for your guidance and support throughout this process. I look forward to hearing from you soon.

Sincerely,

Dr. Lijun Yin 

Assistant Professor

School of Sports, Shenzhen University

yinlijun@szu.edu.cn

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have done quite an amount of work for this revised manuscript. They have sufficiently addressed those concerns that I have raised for their previous version of manuscript. No further comments from me. 

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript is suitable for publication in IJMS in its current form.