Resistin in Tissue Remodeling and Fibrosis: A New Frontier

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This review describes the role of resistin in the development of fibrosis-associated diseases. The article is highly relevant, as the influence of adipose tissue hormones on the development of fibrosis and the adipogenic-myofibroblast differentiation switch has come to be seen as a promising target for fibrosis management. However, several issues are proposed for consideration to improve the quality of the manuscript:
1 Given that the primary cellular source of resistin differs between laboratory animals and humans, does this affect protein concentrations in various tissues?
2 It would be interesting to identify organ-specific and organ-general mechanisms of resistin's influence on the development of fibrosis (Figure 2).
3 What could explain the lack of correlation between resistin levels and patient outcomes in some studies (lines 402-414)?
4 It is known that lipofibroblasts maintain the stability of the alveolar epithelium and their surfactant synthesis in the lungs (https://doi.org/10.1016/j.stem.2016.10.004). Could the pulmonary epithelium stimulate the differentiation of lipofibroblasts into myofibroblasts through resistin secretion (431-436)? 
5 In addition to the table, it is suggested to create a final image or graphical abstract illustrating the authors' idea of ​​the "Fibrotic Switch".

Author Response

We sincerely thank the Reviewer for the time to review our work and to carefully evaluate of our manuscript and for providing constructive comments that helped us improve the quality and clarity of the work. Point-by-point responses are provided. Revisions and corrections that have been made appear in red for easy tracking.

1 Given that the primary cellular source of resistin differs between laboratory animals and humans, does this affect protein concentrations in various tissues?

Theoretically yes, the differing cellular source significantly alters resistin protein concentrations across tissues. In laboratory rodents, resistin is primarily synthesized and stored by white adipocytes, resulting in high baseline concentrations within adipose tissue repositories. Conversely, human resistin expression in mature adipocytes is extremely low to undetectable. Instead, human resistin is predominantly produced by monocytes and macrophages. Consequently, human tissue concentrations are highest in immune-rich organs—such as the spleen and bone marrow—or inside localized, inflamed tissues undergoing heavy macrophage infiltration (e.g., atherosclerotic plaques or fibrotic lesions)

2 It would be interesting to identify organ-specific and organ-general mechanisms of resistin's influence on the development of fibrosis (Figure 2).

This has been updated accordingly.

3 What could explain the lack of correlation between resistin levels and patient outcomes in some studies (lines 402-414)?

This can be explained by several confounding biological and analytical factors:

• Disease heterogeneity, not all patients have the same disease severity.
• Renal Clearance Variations: Resistin is eliminated through the kidneys. Subtle or unmeasured differences in renal function or glomerular filtration rate (GFR) among patient cohorts skew circulating blood concentrations, masking direct correlations with the primary disease outcome.
• Molecular form heterogeneity: Circulating resistin exists in multiple structural isoforms, specifically high-molecular-weight hexamers and low-molecular-weight trimers. Trimers are highly bioactive, but standard commercial ELISA kits often measure total resistin concentration, obscuring the relationship between the active hormone fraction and clinical progression.

4 It is known that lipofibroblasts maintain the stability of the alveolar epithelium and their surfactant synthesis in the lungs (https://doi.org/10.1016/j.stem.2016.10.004). Could the pulmonary epithelium stimulate the differentiation of lipofibroblasts into myofibroblasts through resistin secretion (431-436)? 

We thank the reviewer for bringing up this important point. We have added discussion about the potential role of lipofibroblasts.

5 In addition to the table, it is suggested to create a final image or graphical abstract illustrating the authors' idea of ​​the "Fibrotic Switch".

We have added a new table. The graphical abstract has been included in the initial submission; not sure why the journal did not provide it for review. We are including it again in the revised version.

Reviewer 2 Report

Comments and Suggestions for Authors

The submitted paper outlines a compelling conceptual framework that proposes a paradigm shift for the adipokine resistin—moving its primary pathogenic identity from a well-established pro-inflammatory mediator to a direct driver of tissue remodeling and fibrosis. The authors highlight the species-specific cellular origins of resistin (immune cells in humans vs. adipocytes in rodents), identify its primary receptors (CAP1 and TLR4), and argue that its direct activation of stromal cells (such as fibroblasts) drives the extracellular matrix deposition underlying progressive organ dysfunction in metabolic diseases like NASH, cardiac fibrosis, and diabetic nephropathy. However, a few areas require refinement to ensure the "paradigm shift" argument lands with maximum authority and precision:

1. Consider framing the contrast around the mechanism rather than just the severity of pathogenesis.
2. Update "non-alcoholic steatohepatitis" to "metabolic dysfunction-associated steatohepatitis (MASH)" to ensure the review aligns with current 2026 diagnostic nomenclature.

Author Response

We sincerely thank the reviewer for the time and careful evaluation of our manuscript and for providing constructive comments that helped us improve the quality and clarity of the work. Point-by-point responses are provided. Revisions and corrections have been made accordingly in the revised manuscript that appear in red for easy tracking.

Comment 1: Consider framing the contrast around the mechanism rather than just the severity of pathogenesis.

We thank the reviewer for the suggestion; we did that in the revised manuscript.

Comment 2: Update "non-alcoholic steatohepatitis" to "metabolic dysfunction-associated steatohepatitis (MASH)" to ensure the review aligns with current 2026 diagnostic nomenclature

Correction made.

Reviewer 3 Report

Comments and Suggestions for Authors

This review addresses an interesting and emerging topic, namely the role of resistin as a mediator of tissue remodeling and fibrosis across multiple organ systems. The manuscript is generally well organized, clearly written, and supported by a substantial body of literature. The proposed concept that resistin may function as a "fibrotic switch" linking chronic inflammation with progressive organ fibrosis is timely and potentially valuable. The inclusion of mechanistic pathways and organ-specific evidence enhances the translational relevance of the review. However, certain conceptual, methodological, and interpretative issues should be addressed before publication. In its current form, the review occasionally overstates the strength of available evidence and does not always sufficiently distinguish between direct evidence involving human resistin and indirect evidence derived from resistin-like molecules (RELM/FIZZ family members) in animal models. Addressing these issues would substantially improve the scientific rigor and translational value of the manuscript.

• The main premise of the review is that resistin functions as a direct fibrogenic mediator rather than merely a pro-inflammatory adipokine. While intriguing, the evidence supporting this paradigm shift remains inconsistent across organs. For example, in cardiac fibrosis, several mechanistic studies support a direct profibrotic role. In liver fibrosis, multiple studies report positive associations, whereas others find no association between circulating resistin and fibrosis severity. In pulmonary fibrosis, much of the evidence derives from RELMα, RELMβ, or FIZZ proteins rather than human resistin itself.. In renal fibrosis, most studies demonstrate associations with CKD severity and inflammation rather than direct fibrotic mechanisms. The authors should critically discuss these inconsistencies and avoid presenting the "fibrotic switch" hypothesis as an established concept.
• A recurring issue throughout the manuscript is the integration of evidence from human resistin, murine resistin, RELMα/FIZZ1, RELMβ/FIZZ2, and RELMγ. These proteins have distinct expression patterns and biological functions. The pulmonary fibrosis section is particularly problematic because many cited studies evaluate RELMα or RELMβ rather than resistin itself. The authors should clearly separate evidence derived from human resistin versus RELM proteins, emphasize limitations of extrapolating RELM findings to human resistin biology, and indicate throughout tables and figures whether findings are based on resistin or other RELM family members.
• The manuscript appropriately includes a section comparing human and mouse resistin. However, the implications of these differences for fibrosis research are not adequately discussed. Since murine resistin originates mainly from adipocytes, and human resistin originates predominantly from monocytes/macrophages, the translational relevance of many rodent studies is uncertain. The review would benefit from a dedicated subsection discussing limitations of murine models, challenges in translating findings to humans, anmd emerging humanized models of resistin biology.
• Most mechanistic studies support profibrotic actions of resistin, yet clinical data remain largely associative. The review should more clearly distinguish mechanistic evidence, biomarker studies, and causal evidence. A summary table ranking evidence strength (experimental, translational, clinical) would greatly improve the manuscript.
• The section on therapeutic implications is relatively brief considering the central translational focus of the review. The authors should discuss feasibility of anti-resistin antibodies, CAP1 targeting, TLR4 inhibition, safety concerns, potential off-target effects, and whether any anti-resistin strategies have entered preclinical or clinical development.
• Although this is a narrative review, the manuscript does not describe databases searched, search terms, inclusion criteria, time period covered. A brief methodology section would improve transparency and reproducibility.
• Section 5 is organized by organ system, which is logical. However, the discussion becomes repetitive. Consider restructuring each organ-specific section into experimental evidence, clinical evidence, remaining controversies. This would improve readability.
• The "fibrotic switch" concept is interesting but remains speculative. The manuscript should explicitly state: "This model represents a conceptual framework based on currently available evidence and requires validation in longitudinal and mechanistic studies."
• The abstract occasionally uses strong causal language such as "direct driver of tissue remodeling and fibrosis". Consider replacing with "potential mediator of tissue remodeling and fibrosis" until stronger causal evidence becomes available.
• The manuscript would benefit from inclusion of several recent studies (2024–2026) examining adipokines and fibrosis, macrophage-derived resistin, CAP1 signaling, fibrosis biomarkers.

Author Response

We sincerely thank the reviewer for the time and for the extensive evaluation of our manuscript and for providing constructive comments that helped us improve the quality and clarity of the work. Point-by-point responses are provided. Revisions and corrections made appear in red for easy tracking.

• The authors should critically discuss these inconsistencies and avoid presenting the "fibrotic switch" hypothesis as an established concept.

We have rediscussed the concept and revised it accordingly.

• A recurring issue throughout the manuscript is the integration of evidence from human resistin, murine resistin, RELMα/FIZZ1, RELMβ/FIZZ2, and RELMγ.

We have separated the contribution and the role of each of these molecules and flamed the discussion accordingly. We also I tried to incorporate all of these points into the revised figure 2.

• The review would benefit from a dedicated subsection discussing limitations of murine models, challenges in translating findings to humans, and emerging humanized models of resistin biology.

We thank the reviewer for the suggestion. We have added the suggested limitations section.

• A summary table ranking evidence strength (experimental, translational, clinical) would greatly improve the manuscript.

We thank the reviewer for the suggestion. We have added table 2 in the revised manuscript.

• The section on therapeutic implications is relatively brief considering the central translational focus of the review. The authors should discuss feasibility of anti-resistin antibodies, CAP1 targeting, TLR4 inhibition, safety concerns, potential off-target effects, and whether any anti-resistin strategies have entered preclinical or clinical development.

We thank the reviewer for the comment and the suggestion. We have expanded this section significantly and discussed the potential resistin therapies.

• Although this is a narrative review, the manuscript does not describe databases searched, search terms, inclusion criteria, time period covered. A brief methodology section would improve transparency and reproducibility.

We thank the reviewer for the suggestion. We have added the suggested information in a section titled:  “Literature Search and Evidence Selection”.

• Section 5 is organized by organ system, which is logical. However, the discussion becomes repetitive. Consider restructuring each organ-specific section…

We thank the reviewer for the suggestion. This section has been updated accordingly.

• The "fibrotic switch" concept is interesting but remains speculative. The manuscript should explicitly state: "This model represents a conceptual framework based on currently available evidence and requires validation in longitudinal and mechanistic studies."

We thank the reviewer for the suggestion. This statement has been added as requested.

• The abstract occasionally uses strong causal language such as "direct driver of tissue remodeling and fibrosis". Consider replacing with "potential mediator of tissue remodeling and fibrosis" until stronger causal evidence becomes available.

We agree. The abstract has been revised accordingly.

• The manuscript would benefit from inclusion of several recent studies (2024–2026) examining adipokines and fibrosis, macrophage-derived resistin, CAP1 signaling, fibrosis biomarkers.

We added several recent references (mostly from 2024–2026) as suggested. However, we tried not to include recent papers simply for the sake of adding new citations and instead focused on studies that genuinely strengthened the discussion without moving too far away from the main topic. In addition, in many cases it is necessary to cite original studies rather than relying solely on more recent review articles. It is my habit that, from a scholarly standpoint, citing primary sources ensures that the original contributors receive appropriate recognition for their work.

 

Round 2

Reviewer 3 Report

Comments and Suggestions for Authors

The authors have significantly revised and improved their manuscript. From my point of view, one minor revision should be addressed. The authors should increase the resolution quality of Figure 1. They should also increase the size of the words inside this figure.