Neutrophils and Neutrophil Extracellular Traps in Hepatic Ischemia–Reperfusion Injury: Molecular Mechanisms and Therapeutic Strategies
Round 1
Reviewer 1 Report
Comments and Suggestions for AuthorsI was very pleased to read the review by the esteemed Furong Xu and colleagues. The article addresses the important and timely topic of neutrophil-mediated mechanisms in hepatic ischemia‑reperfusion injury (HIRI). In recent years, neutrophils have attracted considerable attention, and it is increasingly clear that these cells remain far from fully understood and are still underestimated as a therapeutic target. Neutrophils are rapidly responding, short-lived cells equipped with powerful toxic effector mechanisms, including elastases, reactive oxygen species and neutrophil extracellular traps (NETs). They are capable of polarizing into at least two distinct phenotypes. This functional polarity justifies viewing them as a double‑edged sword of the immune system. In many settings, it is precisely neutrophil dysregulation that underlies adverse outcomes. Therefore, I consider the authors’ review to be highly interesting and very timely.
The review presents an exceptionally large body of important, well‑organized information. Its significance extends well beyond the field of liver injury; the concepts and data discussed will be valuable for understanding the biochemistry and physiology of neutrophils in other pathological conditions. The article is clearly structured; in addition to the Introduction and Conclusions, the main text is organized into six core sections. It consistently discusses: the neutrophil recruitment cascade in hepatic ischemia‑reperfusion Injury; key intracellular signaling pathways regulating neutrophil activation and migration; neutrophil extracellular traps (NETs) in hepatic ischemia‑reperfusion Injury; neutrophil intercellular interaction network in hepatic ischemia‑reperfusion injury; functional duality of neutrophils and inflammation resolution; and therapeutic strategies and clinical translation challenges. The review fully matches its stated aim and provides a comprehensive coverage of the topic.
Over the past years, numerous studies and several good reviews have been published in this area; however, the combination of HIRI + neutrophils + NETs + Mac‑1–Syk + translational barriers within one coherent article is both new and original. The uniqueness of this work lies in the way it links HIRI to neutrophil recruitment cascades and intracellular signaling networks centered on Mac‑1–Syk, dissects the temporal dynamics of NET formation in HIRI and the multimodal mechanisms of organ damage, and analyzes inflammatory crosstalk between neutrophils, platelets, endothelial cells and macrophages in the liver specifically in the context of transplantation and major hepatectomy. On this basis, the authors propose a NET‑centered, sequential, multi‑target combination strategy and discuss translational bottlenecks for key therapeutic targets, which represents an important conceptual advance compared with existing literature.
The review cites 163 references, with almost 60% of them published within the last five years, thereby providing the most up‑to‑date synthesis of the field. The conclusions drawn by the authors are well justified and clearly supported by the cited studies. The manuscript includes four excellent original figures illustrating the principal neutrophil‑mediated mechanisms and one integrative summary table, which greatly facilitate comprehension of complex processes. I highly value the work presented by the authors and strongly believe that it deserves publication.
However, I have several minor comments that I would ask the authors to take into consideration.
1. In the reference list, please translate the titles of references 1 and 115 from Chinese into English.
2. In the statement of the study purpose, please explain how the present review differs from three competing reviews published in 2026 on the same topic: Mechanistic insights into neutrophil involvement in liver transplant ischemia-reperfusion injury and rejection (doi: 10.3389/fimmu.2026.1754165), Dynamic regulation and targeted intervention of neutrophils in hepatic ischemia-reperfusion injury (Review) (doi: 10.3892/ijmm.2026.5780), and Bimodal regulation and precision therapy of neutrophil extracellular traps in liver ischemia-reperfusion injury: recent advances (doi: 10.3389/fimmu.2026.1796360).
3. There is duplicated text in Section 3.2.3 (NF-κB): the introductory description of this pathway is presented twice in immediate succession in almost identical wording.
4. Section 8 (Future Directions) is too brief and largely repeats the content of Section 7. It would be more appropriate to retitle this section as “Conclusions.”
Author Response
We sincerely appreciate the reviewer’s valuable and insightful comments, which have greatly improved the scientific rigor and completeness of our manuscript. Detailed point-by-point responses and corresponding revisions are listed in the attached response letter. We wish you smooth work.
Author Response File: 
Author Response.pdf
Reviewer 2 Report
Comments and Suggestions for AuthorsIt is recommended to condense the overly lengthy abstract by trimming redundant background descriptions, highlighting core innovative points including the Mac‑1‑Syk axis, sequential formation pathways of neutrophil extracellular traps, and sequential multi‑target therapeutic strategies, while streamlining the wording to enhance clarity and conciseness. The dense English labels in Figures 1 to 4 should be simplified, with clear legends supplemented and the relationships between molecules and signaling pathways reorganized to improve readability for a wider readership. Conflicting research findings regarding key targets such as Mac‑1, Syk, and PI3K can be extracted and integrated into a dedicated subsection to strengthen the critical analysis nature of this review. Scattered clinical translation bottlenecks should be consolidated into an independent section, categorized according to infection risk, target non‑specificity, limitations of animal models, and optimal therapeutic window issues for more focused presentation. The three NETosis pathways, namely the early rapid vital pathway within 0–60 minutes, the mid-to-late classical suicidal pathway peaking at 2–4 hours, and the infection-associated caspase-11/GSDMD-dependent pathway, can be displayed in a timeline or table format to clearly clarify their temporal sequence, triggering factors, core molecules, and corresponding injury mechanisms. The lengthy descriptions of neutrophil-platelet, neutrophil-endothelial cell, and neutrophil-macrophage crosstalk can be condensed, retaining only core molecular pairs such as P‑selectin/PSGL‑1 and Mac‑1/ICAM‑1, while removing redundant details about natural killer cells. Table 1 needs to be improved by adding missing columns including clinical phase, safety profile, and representative drugs, and clearly distinguishing preclinical, Phase I, and Phase II stages for more intuitive comparison. Overly long and awkward sentences translated literally from complex English structures should be split, and the wording polished to conform to the expression norms of standard academic English and improve overall readability. The vague future research directions in Section 8 should be replaced with 3 to 5 practical and feasible priorities, such as the construction of neutrophil-specific gene knockout models, nanodelivery systems of PAD4 inhibitors, and the development of dynamic NET biomarkers, to avoid empty and general statements. In addition, the reference format needs to be fully standardized, complete missing page numbers and DOI information, eliminate low-relevance or non-English citations, and ensure strict compliance with the journal’s formatting requirements to enhance the academic standardization of the full text.
Author Response
We sincerely appreciate the reviewer’s valuable and insightful comments, which have greatly improved the scientific rigor and completeness of our manuscript. Detailed point-by-point responses and corresponding revisions are listed in the attached response letter. We wish you smooth work.
Author Response File: Author Response.pdf
