Russian Dolls of Heme Metabolism in Malaria-Infected Red Blood Cells: Nested Vulnerabilities and Therapeutic Opportunities
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsThis is a well written review and easy to read. However, the following minor issues may need to be addressed before publication.
- The manuscript alternates between “infected RBCs” and “iRBCs.” Standardising terminology would improve readability.
- Define key abbreviations RSA at first appearance.
- Lines 301 to 306 the sentence is too long and should be split into two or more sentences for clarity.
- There are a lot of one sentence paragraphs in the manuscript which can easily be incorporated into either preceding or proceeding paragraphs.
Author Response
Please see the attachment
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsThis review article employs a nested metabolic model: it proposes a "Russian nesting doll" style theory of heme metabolism (residual host red blood cell metabolism → self-synthesis by the parasite → digestion and release of hemoglobin), providing a new framework for understanding the complex metabolic network of malaria parasites. The overall framework is clear, the concept is novel, and it closely addresses the clinical resistance issues. It has certain academic reference value. However, there are some shortcomings.
1.There is an issue with the integrity of the evidence chain：The core argument of "hemoglobin flux vs. total amount" lacks quantitative support. The causal chain between K13 resistance and hemoglobin metabolism is incomplete. The mechanism by which PPIX amplifies oxidative stress and enhances artemisinin efficacy is too general. The explanation for "excessive hemoglobin inhibits artemisinin" is not in-depth.
2.Limitations of the theoretical model: (1) Ambiguous quantitative boundaries: The quantitative contributions of each metabolic layer (such as the self-synthesis of parasites vs. heme from the host) are not clearly defined (lines 74-75), and this needs to be verified through isotope labeling experiments. (2) Insufficient explanation of drug resistance: Whether artemisinin resistance is related to the change in heme compartmentalization has not been deeply discussed (it could be associated with the impact of Kelch13 mutations).
3. Defects in chart and data presentation: Chart 1B lacks hierarchical annotations for its nested structure, and Chart 2 has a weak connection to the core theme, without a summary chart or mechanism model chart.
4.Inadequate systematicity of terms ：Question: Examples of mixing concepts: For instance, "free heme" (p6), "unbound iron" (p7).
5. Weak association analysis of drug resistance: Question: Not discussed: (1) Changes in the heme compartmentalization of the Kelch13 mutant strain (existing studies suggest that changes in the pH of food vesicles affect heme crystallization). (2) Potential impact of PfCRT transporter variations on the efflux of PPIX.
6.The entire text needs to be polished.
/
Author Response
Please see the attachment
Author Response File: Author Response.pdf
Round 2
Reviewer 2 Report
Comments and Suggestions for AuthorsThis review article employs a nested metabolic model: it proposes a "Russian nesting doll" style theory of heme metabolism (residual host red blood cell metabolism → self-synthesis by the parasite → digestion and release of hemoglobin), providing a new framework for understanding the complex metabolic network of malaria parasites. The overall framework is clear, the concept is novel, and it closely addresses the clinical resistance issues. It has certain academic reference value.Some issues have been largely resolved. It is recommended to proceed with publication.
Comments on the Quality of English Language/
