Comprehensive Roles of ZIP and ZnT Zinc Transporters in Metabolic Inflammation

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review describes zinc transporters, imbalance of these transporters and Metaflammation, and potential therapeutic strategies. It is thorough and comprehensive, and I only have the below minor comments.

1. Section 2.2: Do metallothioneins bind other metal ions as well, or are they specific to zinc?
2. Section 2.3: Check for consistency for spaces between sub-sub headings.
3. Table 1: Check for font and size consistency.
4. Is there any redundancy for the Zip and Znt proteins? If there is a deficiency in one, could another help mitigate any effects?

Author Response

1. Section 2.2: Do metallothioneins bind other metal ions as well, or are they specific to zinc?

Ans: Thank you for this insightful comment. Metallothioneins (MTs) are not specific to zinc; their cysteine-rich thiolate clusters enable high-affinity binding to multiple metal ions, serving dual roles in essential metal homeostasis (Zn²⁺, Cu⁺) and detoxification of toxic metals (Cd²⁺, Hg²⁺, Ag⁺, etc), which has been addressed in Section 2.2.

2. Section 2.3: Check for consistency for spaces between sub-sub headings.

Ans: Thank you for noting this formatting detail. We have reviewed Section 2.3 and confirmed consistent spacing between sub-subheadings (e.g., Endoplasmic Reticulum (ER):, Golgi Apparatus:, etc.). All use single line breaks with uniform indentation. Minor adjustments made in the revised manuscript to ensure exact alignment in the whole document.

3. Table 1: Check for font and size consistency.

Ans: Thank you for noting this formatting detail. All cells now use a consistent font, single-line spacing, 

4. Is there any redundancy for the Zip and Znt proteins? If there is a deficiency in one, could another help mitigate any effects?

Ans: Thank you for this excellent question. While ZIP (influx) and ZnT (efflux) families exhibit limited functional redundancy due to opposing roles in zinc homeostasis, partial compensation occurs within each family under deficiency/stress which has been Addressed in the 2.1 section.

Reviewer 2 Report

Comments and Suggestions for Authors

The manuscript entitled “Comparative Roles of ZIP and ZnT Zinc Transporters in Metabolic 2 Inflammation” provided the overview of ZIP and zinc transporters in function, regulation, and the interactive cross in metabolic dysfunction. Review is quite interesting, but still has lots of scope to intensify the reader’s interest.

1. Title should be comprehensive rather than Comparative.
2. Author must address about the birth of inflammation due to metabolic dysfunction focusing the key metabolic pathways.
3. Author must elaborate the review article in sub heading specify the Roles of ZIP and ZnT Zinc Transporters in disease conditions such as type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), and obesity.

Comments on the Quality of English Language

The manuscript entitled “Comparative Roles of ZIP and ZnT Zinc Transporters in Metabolic 2 Inflammation” provided the overview of ZIP and zinc transporters in function, regulation, and the interactive cross in metabolic dysfunction. Review is quite interesting, but still has lots of scope to intensify the reader’s interest.

1. Title should be comprehensive rather than Comparative.
2. Author must address about the birth of inflammation due to metabolic dysfunction focusing the key metabolic pathways.
3. Author must elaborate the review article in sub heading specify the Roles of ZIP and ZnT Zinc Transporters in disease conditions such as type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), and obesity.

Author Response

1. Title should be comprehensive rather than Comparative.

Ans: Thank you for this suggestion. We agree that the title should comprehensively reflect the review's broad scope covering ZIP/ZnT functions, regulation, crosstalk, and therapeutic implications in metabolic inflammation, rather than emphasizing "Comparative" aspects.

2. Author must address about the birth of inflammation due to metabolic dysfunction focusing the key metabolic pathways.

Ans: Thank you for this valuable suggestion. We have expanded Section 3 (Functional Links Between Zinc and Metaflammation) by addressing this point how metabolic dysfunction triggers inflammation.

3. Author must elaborate the review article in sub heading specify the Roles of ZIP and ZnT Zinc Transporters in disease conditions such as type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), and obesity.

Ans: We thank the reviewer for this suggestion and agree that explicitly highlighting the disease relevance of ZIP and ZnT transporters strengthens the clinical translational focus of the review. The roles of these transporters in T2D (ZnT8 in β-cell insulin secretion, ZIP14/ZnT7 in hepatic insulin sensitivity), NAFLD (ZIP14-driven hepatic steatosis and insulin resistance, ZnT8 protective effects), and obesity (ZIP14/ZIP13 in adipose inflammation and browning suppression) are already comprehensively addressed throughout Sections 4 (tissue-specific roles) and 5 (signaling pathways), where the mechanistic evidence is presented in detail with primary literature support.

 

 

Reviewer 3 Report

Comments and Suggestions for Authors

The manuscript is well-structured and comprehensive, summarizing the role of ZIP and ZnT transporters in metabolic inflammation. The literature coverage was very well compiled and read enjoyably.  Although several review articles in the literature address zinc transporters (ZIP/ZnT), zinc homeostasis, and metabolic inflammation, none combine all topics exactly the way this manuscript does. Nevertheless, the following points must be addressed in order the review to become more critical, and integrative:
Major Comments:
1.    Overgeneralized mechanistic claims
•    Lines 201-207: The cited evidence does not clearly establish causality across tissues, nor does the text explain intermediate mechanistic steps. Provide mechanistic explanation or rephrase to avoid overstating causality.
•    Lines 209–218, 219–222: make broad claims about miRNAs acting as “key post-transcriptional influencers” without explaining mechanistic specificity or conditions under which these miRNAs act. Clarify how each miRNA mechanistically influences inflammatory or metabolic pathways; avoid broad generalizations.
•    Lines 223–228: These lines suggest complex dose-dependent regulation but do not elaborate on what “complex” means or how these effects translate functionally.
•    Lines 406-407: Very generalized statement.
•    Lines 454–472: imply that zinc transporters are viable therapeutic targets and that strategies are emerging toward clinical application. Much of the supporting evidence is preclinical. Moderate the language to avoid overstating translational readiness.
2.    The authors should clearly state how their review differs from the major existing reviews and what new angle it offers.
3.    Lack of synthesis and critical evaluation across sections:
Lines 209–228, 288–305, 306–313: These sections list multiple study findings without synthesizing differences, limitations, or contradictory evidence. A scholarly review should integrate findings, not only compile them. Add critical discussion comparing studies, addressing limitations, and highlighting unresolved questions.
4.    Missing conceptual figures: 
The manuscript would benefit greatly from the inclusion of integrative schematics, such as:
•    A schematic illustrating ZIP vs ZnT transporter directionality
•    A tissue-level map (pancreas, liver, adipose, immune)
•    A signaling pathway overview
Include at least one or two summary figures.
5.    Define all abbreviations at first mention: e.g. Erp44, UPR, NLRP3, TLR, GSIS etc.
Moderate Comments
6.    Tables are overly dense and difficult to read:
Tables 3 and 4 contain long explanatory sentences within each cell, reducing thus readability and does not help clarity. It is recommended to shorten the table text and move detailed descriptions int the main text.
7.    Repeated reference: Lines 925 and 932: Remove duplicates
8.    Typographical issues:
•    Line 209: “control”
•    Line 211: inchronic
•    Line 298: cyto-kines
•    Several lines show hyphenation artifacts (e.g., inflammation)
•    Line 406: Irrelevant insertion of: Zinc and Metabolic Sensors
9.    Clarity issues:
Lines 117-120: very long sentence; needs splitting

Author Response

Major Comments:
1.    Overgeneralized mechanistic claims
•    Lines 201-207: The cited evidence does not clearly establish causality across tissues, nor does the text explain intermediate mechanistic steps. Provide mechanistic explanation or rephrase to avoid overstating causality.

Ans: We thank the reviewer for this important observation regarding causal language. The cited references primarily provide correlative associations and tissue-specific mechanistic studies rather than pan-tissue causal evidence. To address this, we have revised lines 201-207 (Now 224-230) as follows (tracked changes shown).

• 
     Lines 209–218, 219–222: make broad claims about miRNAs acting as “key post-transcriptional influencers” without explaining mechanistic specificity or conditions under which these miRNAs act. Clarify how each miRNA mechanistically influences inflammatory or metabolic pathways; avoid broad generalizations.

Ans: Lines 209–222 have been revised to replace broad statements about miRNAs as ‘key post-transcriptional influencers’ with concrete mechanistic examples (miR‑675/NF‑κB–STAT3, miR‑21–PDCD4, miR‑34a–SIRT1/Klf4), specifying how each miRNA connects zinc/transporter status to inflammatory and metabolic pathways, thereby avoiding overgeneralization (Section 3.2 tracked changes shown).

• 
     Lines 223–228: These lines suggest complex dose-dependent regulation but do not elaborate on what “complex” means or how these effects translate functionally.

Ans:  We agree that our original wording (‘complex, dose-dependent relationship’) was too general. The text has now been revised to specify how zinc status and miRNA levels interact functionally. We clarify that moderate zinc deficiency reduces miR‑122 expression, altering hepatic lipid handling and circulating lipid profiles, whereas zinc repletion can partially restore miR‑122 and improve aspects of lipid metabolism. We also explicitly describe that zinc excess upregulates miR‑144‑3p, which suppresses the Nrf2 antioxidant pathway and thereby enhances oxidative stress and insulin resistance in hepatocyte and adipocyte models. The revised paragraph (Section 3.2 tracked changes shown) now explains what is meant by ‘complex’ and ‘dose‑dependent’ in terms of directionality and downstream metabolic and inflammatory consequences, avoiding vague generalizations.

• 
     Lines 406-407: Very generalized statement.

Ans: We appreciate the reviewer’s observation. The final two sentences of this paragraph were intended as a brief integrative summary, linking the detailed TLR–NF‑κB–ZIP8/ZIP14 mechanisms described above to the broader immune–metabolic interface, rather than as new generalized mechanistic claims. To avoid any impression of overgeneralization, we have now revised these lines (Section 5.1 tracked changes shown) to explicitly state that zinc and its transporters modulate TLR-driven inflammatory responses within metabolic tissues and connect these to nutrient- and energy-sensing pathways discussed in subsequent sections, instead of implying that zinc functions as a universal metabolic sensor. This keeps the sentences clearly framed as a synthesis of the preceding content while maintaining mechanistic specificity.

• 
     Lines 454–472: imply that zinc transporters are viable therapeutic targets and that strategies are emerging toward clinical application. Much of the supporting evidence is preclinical. Moderate the language to avoid overstating translational readiness.

Ans: We thank the reviewer for this important point. The original wording in this section may have suggested a greater degree of translational maturity than is currently supported by the literature. In the revised version  (Section 6-subsection: tracked changes shown), we now explicitly state that most of the evidence for targeting ZIP5, ZnT8, ZIP13, and ZIP14 comes from genetic and preclinical (cellular and animal) studies, and we avoid language implying imminent clinical application. References to these transporters as “viable therapeutic targets” have been softened to describe them as “promising candidates for future therapeutic targeting” or “attractive experimental targets,” and we clearly note that no approved therapies currently target ZIP13 or ZIP14 in metabolic disease. The example of bortezomib in SCD‑EDS is now presented as a proof‑of‑concept for modulating zinc signaling rather than as a directly translatable metabolic therapy, and we emphasize that substantial additional work is required before these strategies can be considered clinically validated.

2. 
      The authors should clearly state how their review differs from the major existing reviews and what new angle it offers.

Ans: We thank the reviewer for this helpful suggestion. We have now explicitly clarified in the Introduction how this review differs from existing zinc and zinc‑transporter reviews. Specifically, we note that prior articles have generally focused either on systemic zinc status or on individual transporters in isolation, often treating immune and metabolic aspects separately. In contrast, our review integrates organelle‑level zinc trafficking, tissue‑specific roles of both ZIP and ZnT families, and their convergence on metaflammation in key metabolic diseases (T2D, NAFLD, and obesity), and additionally highlights zinc as a second messenger, the zinc–miRNA axis, and transporter‑mediated crosstalk with NF‑κB, NLRP3, and TLR signaling as a unifying framework. This new text has been added to the final paragraph of the conclusion to clearly articulate the distinct angle and added value of our review.

3. 
      Lack of synthesis and critical evaluation across sections:
   Lines 209–228, 288–305, 306–313: These sections list multiple study findings without synthesizing differences, limitations, or contradictory evidence. A scholarly review should integrate findings, not only compile them. Add critical discussion comparing studies, addressing limitations, and highlighting unresolved questions.

Ans: We thank the reviewer for emphasizing the need for synthesis. A comprehensive critical discussion has been added at the end of the 'Tissue-specific roles of zinc transporters' section that integrates findings across studies, addresses model/endpoint variations and human genetic limitations, highlights convergent/divergent transporter roles, and identifies key unresolved questions including tissue-specific zinc optima and translation challenges. This elevates the review from descriptive compilation to analytical synthesis.

4. 
      Missing conceptual figures: 
   The manuscript would benefit greatly from the inclusion of integrative schematics, such as:
   •    A schematic illustrating ZIP vs ZnT transporter directionality
   •    A tissue-level map (pancreas, liver, adipose, immune)
   •    A signaling pathway overview.

Include at least one or two summary figures

Ans: We appreciate the reviewer’s suggestion to include integrative schematics. In the revised manuscript, we have added a signaling overview figure titled ‘Zinc Transporters and Signaling Pathways in Metaflammation’. This figure now (i) distinguishes ZIP‑mediated zinc influx and ZnT‑mediated efflux/sequestration at the plasma and organelle membranes, (ii) depicts key metabolic tissues and cell types (adipocytes, hepatocytes, and β cells) exposed to metabolic stressors such as saturated fatty acids, dyslipidemia, and hyperglycemia, and (iii) integrates zinc ‘waves’, intracellular labile Zn²⁺, and ZIP/ZnT regulation with downstream NF‑κB, MTF‑1, MAPK, and NLRP3 signaling leading to cytokine production and metaflammation. The figure also illustrates the feedback loop whereby cytokines and TLR activation modulate ZIP8/ZIP14 expression and zinc pools, thereby visually summarizing the immune–metabolic crosstalk described in Sections 3–5. This updated schematic directly addresses the request for an integrative signaling pathway overview that explicitly incorporates zinc transporter directionality and tissue‑level context.
.

5. 
      Define all abbreviations at first mention: e.g. Erp44, UPR, NLRP3, TLR, GSIS etc.

And: hank you for this important clarity request. We have systematically defined all abbreviations at first mention throughout the manuscript
Moderate Comments
6.    Tables are overly dense and difficult to read:
Tables 3 and 4 contain long explanatory sentences within each cell, reducing thus readability and does not help clarity. It is recommended to shorten the table text and move detailed descriptions int the main text.

Ans: We appreciate the reviewer’s observation regarding Tables 3 and 4. In the revised manuscript, we have shortened the text within table cells to concise phrases (e.g., key functions, primary disease links).
7.    Repeated reference: Lines 925 and 932: Remove duplicates

Ans:We thank the reviewer for pointing this out. We identified and removed the duplicated reference in the bibliography (previously listed at lines 925 and 932), and have renumbered the reference list and corresponding in‑text citations to ensure that each article now appears only once.
8.    Typographical issues:
•    Line 209: “control”
•    Line 211: inchronic
•    Line 298: cyto-kines
•    Several lines show hyphenation artifacts (e.g., inflammation)
•    Line 406: Irrelevant insertion of: Zinc and Metabolic Sensors

Ans: Thank you for carefully identifying the typographical issues. These have now been corrected throughout the manuscript. Specifically, ‘controll’ at line 209 has been corrected to ‘control’, ‘inchronic’ at line 211 has been corrected to ‘in chronic’, ‘cyto-kines’ at line 298 has been corrected to ‘cytokines’, and hyphenation artifacts introduced during formatting (e.g., ‘inflam-mation’) have been removed. The stray subheading text ‘Zinc and Metabolic Sensors’ at line 406 has also been deleted or repositioned appropriately so that it no longer interrupts the paragraph flow. We have additionally re‑checked the full document for similar typographical and line-break issues
9.    Clarity issues:
Lines 117-120: very long sentence; needs splitting

Ans:Thank you for pointing this out. The sentence spanning lines 117–120 has been rewritten as two shorter sentences to improve clarity and readability while preserving the original meaning (Now 126-130).

 

 

Reviewer 4 Report

Comments and Suggestions for Authors

COMMENT ON MANUSCRIPT- ID 4027603 _Targets

Title: Comparative Roles of ZIP and ZnT Zinc Transporters in Metabolic 2

Inflammation

 

The review manuscript addresses the roles of zinc transporter families in metabolic inflammation. The topic is generally important and timely, and the authors did well in presenting extensive mechanistic detail and comprehensive literature citations. However, the paper might benefit from the suggestions highlighted below.

 

Comments

1. The review is comprehensive but overly lengthy and shows some redundancy that should be addressed. For instance, authors wrote on ZIP14 roles in several tissues, while ZnT8 functions were described multiple times. There are detailed descriptions of organelle-specific zinc functions that are not directly linked to metabolic inflammation.
2. Even though the manuscript has an abundance of details, some narrative in the manuscript might be better framed to incorporate ideas into a more coherent structure. For instance, it will be good if a conceptual figure mapping ZIP/ZnT transporters to metabolic tissues and pathways is provided. Similarly, a subsection briefly talking about overarching principles like zinc as a second messenger or how transporter dysfunction drives metainflammation will be good.
3. The review can be enhanced by giving a more detailed discussion on how both excessively low or high zinc concentrations influence inflammation.
4. Kindly define all abbreviations at first mention while ensuring that the use of terms like “metainflammation,” “metabolic inflammation,” and “chronic low-grade inflammation” is consistent.
5. The manuscript is well-written, but it should be carefully checked line by sentence to correct punctuation and typographical errors.

Author Response

1. The review is comprehensive but overly lengthy and shows some redundancy that should be addressed. For instance, authors wrote on ZIP14 roles in several tissues, while ZnT8 functions were described multiple times. There are detailed descriptions of organelle-specific zinc functions that are not directly linked to metabolic inflammation.

Ans: We thank the reviewer for this constructive comment. We agree that the original version contained some redundancy, particularly in repeated descriptions of ZIP14 and ZnT8 across multiple sections, and that parts of the organelle-focused text could be more tightly linked to metabolic inflammation. In the revised manuscript, we have (i) retained the most complete discussions of ZIP14 (liver) and ZnT8 (pancreatic β cells) in their primary tissue sections and replaced repeated descriptions elsewhere with brief cross‑references to these sections, and (ii) streamlined the organelle-specific zinc trafficking section by trimming purely structural detail and explicitly emphasizing how ER, Golgi, mitochondrial, lysosomal, and vesicular zinc pools contribute to metaflammation in metabolic tissues. We have also removed or consolidated overlapping explanations of shared signaling mechanisms (e.g., NF‑κB and NLRP3 activation), which has reduced length and improved focus while preserving the comprehensive scope of the review.

2. Even though the manuscript has an abundance of details, some narrative in the manuscript might be better framed to incorporate ideas into a more coherent structure. For instance, it will be good if a conceptual figure mapping ZIP/ZnT transporters to metabolic tissues and pathways is provided. Similarly, a subsection briefly talking about overarching principles like zinc as a second messenger or how transporter dysfunction drives metainflammation will be good.

Ans: We thank the reviewer for this excellent suggestion. The concepts of zinc as a second messenger ('zinc waves,' ZIP7 signaling) and transporter dysfunction driving metaflammation (ZIP14 insulin resistance, ZnT8 β-cell defects, NF-κB regulation) were already present across the Introduction, Sections 2.3, and 4-5.

We also appreciate the helpful suggestion regarding conceptual figure. In the revised manuscript, we have added a new conceptual figure that maps key ZIP and ZnT transporters to major metabolic tissues (liver, pancreas, adipose tissue, and immune cells) and their principal signaling pathways (NF‑κB, NLRP3, TLRs, and insulin/PI3K–Akt) involved in metaflammation. The figure visually summarizes how ZIP14, ZnT8, ZIP13/ZIP14, and ZIP8/ZnT1 coordinate zinc flux in these tissues and how these fluxes intersect with inflammatory and metabolic signaling, complementing the detailed descriptions provided in Sections 3–5.

3. The review can be enhanced by giving a more detailed discussion on how both excessively low or high zinc concentrations influence inflammation.

Ans: We thank the reviewer for highlighting this important point. The bidirectional effects of zinc deficiency (NF-κB/NLRP3 activation, M1 polarization) and excess (mitochondrial/lysosomal overload, compartment-specific toxicity) on metaflammation were already noted across Sections 3.1 and 2.3. To make this discussion more prominent and cohesive, we have added a concise new subsection 3.3 "Dual effects of zinc deficiency and excess on metaflammation.

4. Kindly define all abbreviations at first mention while ensuring that the use of terms like “metainflammation,” “metabolic inflammation,” and “chronic low-grade inflammation” is consistent.

Ans: Both terms “metaflammation” and “metabolic inflammation” has been put very carefully. As it has been mentioned in the text, “Research has identified an intricate association between zinc equilibrium and metabolic inflammation, a phenomenon also known as metaflammation, which is a chronic, low-grade inflammatory state arising from metabolic disorders rather than classical infectious triggers.” And in the Table 2 the term “chronic low-grade inflammation” has been mentioned to refere the original research.

5. The manuscript is well-written, but it should be carefully checked line by sentence to correct punctuation and typographical errors.

Ans: Thank you for requesting a thorough line-by-line proofread. We have systematically reviewed the entire manuscript and implemented the finest possible corrections across punctuation, grammar, spacing, and typos.

Round 2

Reviewer 2 Report

Comments and Suggestions for Authors

Authors have revised the manuscript, and it may be accepted for publication. 

Comments on the Quality of English Language

The manuscript entitled “Comparative Roles of ZIP and ZnT Zinc Transporters in Metabolic 2 Inflammation” provided the overview of ZIP and zinc transporters in function, regulation, and the interactive cross in metabolic dysfunction. Review is quite interesting, but still has lots of scope to intensify the reader’s interest.

1. Title should be comprehensive rather than Comparative.
2. Author must address about the birth of inflammation due to metabolic dysfunction focusing the key metabolic pathways.
3. Author must elaborate the review article in sub heading specify the Roles of ZIP and ZnT Zinc Transporters in disease conditions such as type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), and obesity.

Author Response

Reviewer-2

Thank you very much for your positive evaluation and for recommending our revised manuscript for publication. We greatly appreciate the constructive comments provided during the review process, which have significantly improved the clarity and depth of the work.

1. Title should be comprehensive rather than Comparative.

Response: Thank you for this suggestion. We agree that the title should comprehensively reflect the review's broad scope covering ZIP/ZnT functions, regulation, crosstalk, and therapeutic implications in metabolic inflammation, rather than emphasizing "Comparative" aspects.

1. Author must address about the birth of inflammation due to metabolic dysfunction focusing the key metabolic pathways.

Response: Thank you for this valuable suggestion. We have expanded Section 3 (Functional Links Between Zinc and Metaflammation) by addressing this point how metabolic dysfunction triggers inflammation.

1. Author must elaborate the review article in sub heading specify the Roles of ZIP and ZnT Zinc Transporters in disease conditions such as type 2 diabetes (T2D), nonalcoholic fatty liver disease (NAFLD), and obesity.

Response: We thank the reviewer for this suggestion and agree that explicitly highlighting the disease relevance of ZIP and ZnT transporters strengthens the clinical translational focus of the review. The roles of these transporters in T2D (ZnT8 in β-cell insulin secretion, ZIP14/ZnT7 in hepatic insulin sensitivity), NAFLD (ZIP14-driven hepatic steatosis and insulin resistance, ZnT8 protective effects), and obesity (ZIP14/ZIP13 in adipose inflammation and browning suppression) are already comprehensively addressed throughout Sections 4 (tissue-specific roles) and 5 (signaling pathways), where the mechanistic evidence is presented in detail with primary literature support.

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have thoroughly addressed the recommendations. The improved coherence between sections and the addition of critical thinking elements have substantially enhanced the manuscript, elevating it from a descriptive review to a well-integrated analytical synthesis

There is one thing though, that it needs to be attended: The version of the figure I received is missing elements that the authors describe as being included in the figure.

• Arrows from transporters to cytokines to metabolic inflammation
• The feedback loop whereby cytokines and TLR activation modulate ZIP8/ZIP14 expression and zinc pools, thereby visually summarizing the immune–metabolic crosstalk described in Sections 3–5. 

Please also include the Figure legend in the manuscript.

Author Response

Response: We sincerely appreciate the reviewer’s positive assessment of the improved coherence and analytical integration across sections. In response to the present concern about the Figure clarity, we have updated the schematic, addressing the following points mentioned below:

Now clear arrows have been incorporated illustrating the connection from ZIP/ZnT transporters to cytokine production and from cytokines to metaflammation, effectively representing the sequence from zinc flow to intracellular signaling, cytokine output, and chronic inflammation, in alignment with the content in Sections 3–5.

The feedback loops incorporated mentioning  cytokines and TLR activation regulate ZIP expression and intracellular zinc pools in metabolic and immune cells, summarizing the immune-metabolic crosstalk described in the manuscript.​

A detailed figure legend has been inserted in the manuscript to explain these arrows, feedback relationships, and the functions of ZIPs/ZnTs, cytokines, and signaling pathways in metaflammation.​

We hope these revisions fully resolve the concern about missing graphical elements and that the updated figure now accurately reflects the mechanisms described.