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Open research questions in Neutrophil, Myeloperoxidase and Oxidative Mechanisms

47 unresolved questions extracted from the limitations and future-work sections of 257 Neutrophil, Myeloperoxidase and Oxidative Mechanisms papers in our library. Each links back to the study that raised it.

What the literature leaves open

  • Although several studies have demonstrated that various immune cells, such conventional dendritic cells (cDCs), macrophages, monocytes, and marginal zone B cells, co-localize or interact with FVIII, the primary immune cell population mediating FVIII immune recognition remains poorly explored.

    Defining the Primary Immune Cell in the Immune Response to Coagulation Factor VIII 2245246 · 2026 · DOI

  • Abstract Introduction Microthrombus formation is a determinant of COVID-19 severity; however, the in vivo spatiotemporal mechanisms of thrombogenesis remain unclear.

    Neutrophil adhesion to vessel walls impairs pulmonary circulation in COVID-19 pathology 2309432 · 2026 · DOI

  • Neutrophil extracellular traps (NETs) are major pathogenic effectors in chronic systemic lupus erythematosus (SLE) pathogenesis, but how they mediate acute, UVB-triggered skin inflammation and subsequent systemic injury remains poorly defined.

    Neutrophil Extracellular Traps Drive a skin-kidney inflammatory axis in UVB-Irradiated Lupus-Prone Mice · 2026 · DOI

  • Although impaired antifungal immunity has been implicated in IAPA pathogenesis, the cell type-specific immune mechanisms driving susceptibility remain incompletely understood.

    Broad remodeling of the pulmonary immune landscape occurs during IAPA with specific functional deficits of neutrophil subsets · 2026 · DOI

  • However, translating NET-related research into clinical practice faces numerous challenges, including the lack of standardised biomarkers for real-time monitoring of NET levels and preserving the host’s essential anti-infective immune pathways while inhibiting tissue damage.

    Neutrophil extracellular traps and acute kidney injury: a narrative review · 2026 · DOI

  • Although this process involves metabolic reprogramming, the specific underlying metabolic mechanisms of neutrophil N1 polarization within the periodontitis-modified BM niche remain poorly defined.

    CHAC2-mediated glutathione metabolic reprogramming drives N1 polarization of bone marrow neutrophils and exacerbates inflammatory comorbidities · 2026 · DOI

  • Thrombosis remains a life‑threatening complication in hema‑ tological malignancies, with emerging evidence implicating NETs as key mediators through multiple prothrombotic mechanisms. While the involvement of NETs in hypercoagu‑ lability across MPN, AML, MM, HL and ALL is established, 16 LV et al: NETs IN HEMATOLOGIC MALIGNANCY THROMBOSIS their disease‑specific mechanisms require further elucida‑ tion. Current NET‑targeting strategies, including formation inhibition, degradation enhancement and mediator blockade, show preclinical promise but demand rigorous clinical vali‑ dation, particularly regarding bleeding risks in patients with thrombocytopenia. Critical challenges persist in NET quantification and biomarker development. Future directions should priori‑ tize i) standardized NET detection assays, ii) mechanistic studies on NET‑driven thrombosis, iii) therapeutic optimi‑ zation through targeted NETosis inhibition or combination approaches and iv) integration of NET biomarkers into risk stratification models. Addressing these priorities through collaborative research will accelerate the translation of NET‑focused strategies into clinical practice, offering novel avenues for thrombosis management in hematological malignancies.

    Neutrophil extracellular traps in thrombosis of hematologic malignancies: Underlying mechanisms and therapeutic opportunities (Review) · 2026 · DOI

  • 1. Introduction Patients with cancer face a substantially elevated risk of venous thromboembolism (VTE), with incidence rates 4‑7‑fold higher than those observed in the normal popula‑ tion (1,2). Furthermore, the coexistence of VTE further worsens the clinical outcomes of patients with cancer (3). While thrombotic complications have historically been asso‑ ciated mainly with solid tumors, hematological malignancies have typically been characterized by bleeding tendencies and overt disseminated intravascular coagulation (DIC). However, contemporary data indicate that the incidence of VTE in patients with hematological malignancies is compa‑ rable to that observed in patients with solid tumors at high risk of thrombosis (4). The high incidence of thrombosis is closely related to the hypercoagulable state of the tumor itself, treatment‑related factors (such as chemotherapy and central venous catheterization), and the patient's own factors (such as advanced age and long‑term bed rest) (5). Additionally, a common treatment course for patients with hematological malignancies consists of aggressive chemotherapy followed by hematopoietic stem cell (HSC) transplantation. This regimen frequently causes long‑lasting and severe pancytopenia (4). Given these challenges, there is a paucity of accumulated clinical expertise concerning the prevention and treatment of thrombotic events in individuals with hematological malignancies. 2 LV et al: NETs IN HEMATOLOGIC MALIGNANCY THROMBOSIS Through the extrusion of neutrophil extracellular traps (NETs), which are thread‑like structures composed of chro‑ matin, neutrophils are able to eliminate invading microbes (6). NET formation leads to a unique cell death process called NETosis (7). Previous studies have shown that intravascular NETs promote coagulation and thrombosis by activating the clotting cascade and interacting with platelets, playing a key role in immunothrombosis (8‑11). Excessive immunothrom‑ bosis triggers thromboinflammation, driven by endothelial dysfunction, dysregulated coagulation, complement activation, platelet activation and leukocyte recruitment (12). In sterile inflammation, such as in hematological malignancies, NET‑mediated thrombosis can cause tissue ischemia. For example, the Jak2V617F mutation in myeloproliferative neoplasms (MPNs) was shown to increase thrombosis by enhancing NET formation (13). Disrupting NETs [for example with deoxyribonuclease (DNase)] can reduce clotting and thrombotic events (14). Understanding the mechanisms of thromboinflammation is crucial, as current anticoagulants only partially prevent thrombosis while increasing bleeding risk, particularly in thrombocytopenic hematological malig‑ nancies (15). The present review explores the role of NETs in thrombosis and potential therapeutic strategies.

    Neutrophil extracellular traps in thrombosis of hematologic malignancies: Underlying mechanisms and therapeutic opportunities (Review) · 2026 · DOI

  • Cardiovascular complications increase COPD morbidity and mortality, but mechanistic links between airway injury and vascular dysfunction remain unclear, largely due to limitations of in vitro models that fail to replicate the multicellular lung environment.

    Organ on chip model of respiratory vascular interactions under COPD relevant oxidative stress · 2026 · DOI

  • BackgroundDiabetes mellitus (DM) worsens pulmonary tuberculosis (TB) and drives systemic hyper-inflammation, but the underlying mechanisms remain unknown.

    Neutrophil-primed immunopathology in poorly-controlled diabetes worsens matrix destruction in pulmonary tuberculosis · 2026 · DOI

  • Prior studies have shown that mucin glycoproteins secreted in the oral cavity and cervicovaginal tract can modulate NETosis, but it remains unknown whether mucins secreted in the respiratory tract influence NET formation.

    Airway mucins function as endogenous inhibitors of neutrophil extracellular traps · 2026 · DOI

  • Since the potential therapeutic effects beyond endotoxin adsorption remain unclear, we investigated the in vitro adsorption of various leukocyte subtypes using PMX columns under controlled stimulation.

    Removal of activated neutrophils by a polymyxin B-immobilized fiber (PMX) column · 2026 · DOI

  • Future research should focus on clarifying underlying disease mechanisms, refining classification criteria, and developing therapeutic strategies that address both the fibrotic and autoimmune components of this complex condition [3,21]. Despite growing recognition of this entity, the current body of evidence remains limited by the predominance of retrospective studies, small sample sizes, and substantial heterogeneity in diagnostic definitions and outcome reporting [3,21].

    Myeloperoxidase Antineutrophil Cytoplasmic Antibody (MPO-ANCA)-Associated Usual Interstitial Pneumonia: Pathogenic Mechanisms, Diagnostic Challenges, and Clinical Implications · 2026 · DOI

  • In summary, this review highlights several key findings regarding the dual role of NETs in gout. During the acute phase, NETs help limit inflammation by forming aggNETs that sequester MSU crystals and degrade inflammatory mediators; however, they can also amplify inflammatory cascades via complement and inflammasome activation. In the chronic phase, impaired clearance leads to persistent NET accumulation, which serves as a structural scaffold for tophus formation and promotes bone erosion by disrupting the bone metabolic axis. Thus, the NET function varies with disease stage and local microenvironment. Regarding the mechanisms of NET formation, three main types of NETosis have been identified—suicidal, vital, and mitochondrial DNA release— with MSU crystals primarily triggering ROS-dependent suicidal NETosis, while alternative pathways (e.g., Src/Syk and RIPK1- RIPK3-MLKL signaling) are also involved. Notably, all major types of NETosis begin with PAD4-mediated histone citrullination, a critical initiating step. Finally, In gout, inflammatory regulation and tissue damage involve complex interactions among multiple pathways and cell types. Positive feedback loops develop between NETs, macrophages, and synovial fibroblasts, while internal resolution mechanisms—including immune silencing by aggNETs—are also activated. NETs contribute to bone erosion through several methods: directly damaging bone cells, disrupting the OPG/ RANKL/RANK axis, and increasing cartilage matrix breakdown. Precisely modulating the balance between NET formation and clearance to achieve two key therapeutic goals—controlling acute inflammation while promoting tophus dissolution and bone repair during the chronic phase—remains a major challenge in gout management. Further studies are warranted to dissect the dynamic regulatory mechanisms of NETs across distinct stages of gout and to develop targeted intervention strategies with high specificity and stage adaptability. Such advances will drive the evolution of gout management from symptomatic control toward the restoration of immune homeostasis. To achieve this transition, researchers must overcome three major bottlenecks: First, they must comprehensively delineate the dynamic evolutionary patterns of NETs at different disease stages. Second, they must establish organoid or microfluidic models that recapitulate human pathological features, thereby enabling visual tracking of the entire NET formationclearance cycle. Third, they must implement precision diagnostic and therapeutic systems based on NET subtyping in clinical translation, liquid biopsies, and functional assays to guide personalized interventions. Only through these approaches can the field shift from global immunosuppression to stage-specific immunomodulation, transforming the double-edged sword of NETs into a controllable therapeutic tool and opening new avenues for the management of gout and other autoimmune disorders.

    Neutrophil extracellular traps in gout: from immune defense to pathological dynamic equilibrium · 2026 · DOI

  • While the study established that elevated NETs expression in HNSCC tissues correlates with tumor progression, the specific spatial distribution of NETs within the tumor microenvironment (perivascular regions, tumor core versus invasive margin) and their heterogeneity across different HNSCC subtypes and stages remains uncharacterized.

    Cationic nanoparticles with disrupting neutrophil extracellular traps inhibit the progression of head and neck squamous cell carcinoma · 2026 · DOI

  • The biosafety evaluation of cNP was limited to cytotoxicity assessment in SCC9 cells via CCK-8 assay; comprehensive evaluation of cNP biocompatibility should include systemic toxicity studies, organ-specific accumulation analysis, and immunogenicity assessment in the in vivo tumor-bearing mouse model to ensure clinical translatability.

    Cationic nanoparticles with disrupting neutrophil extracellular traps inhibit the progression of head and neck squamous cell carcinoma · 2026 · DOI

  • The study documented that cNP plus anti-PD-1 reduced regulatory T cells, M2 macrophages, and M-MDSCs while increasing CD8+ T cells and B cells, but the specific molecular mechanisms by which NET-DNA clearance mediates macrophage polarization from M2 to M1 phenotype and suppresses myeloid inflammation require mechanistic investigation.

    Cationic nanoparticles with disrupting neutrophil extracellular traps inhibit the progression of head and neck squamous cell carcinoma · 2026 · DOI

  • The in vivo efficacy of cNP combined with anti-PD-1 was demonstrated only in a C3H tumor-bearing mouse model; validation in additional HNSCC xenograft or syngeneic models with different genetic backgrounds and in spontaneous tumor models would strengthen the generalizability of the combination therapy approach.

    Cationic nanoparticles with disrupting neutrophil extracellular traps inhibit the progression of head and neck squamous cell carcinoma · 2026 · DOI

  • While the study demonstrated that NET-DNA at 1 μg/mL significantly enhanced SCC9 cell migration in wound-healing assays, the concentration-dependent relationship between NET-DNA levels and tumor cell migratory capacity across different HNSCC cell lines remains unexplored, requiring additional migration and invasion assays at multiple NET-DNA concentrations.

    Cationic nanoparticles with disrupting neutrophil extracellular traps inhibit the progression of head and neck squamous cell carcinoma · 2026 · DOI

  • The study evaluated NET-DNA effects on HNSCC cell proliferation only within a narrow concentration range (0, 0.5, 1, and 2 μg/mL) across four cell lines (SCC9, SCC15, Cal27, Cal33); systematic dose-response characterization across a broader concentration spectrum and additional HNSCC cell lines is needed to establish the threshold concentration at which NET-DNA directly stimulates tumor cell proliferation.

    Cationic nanoparticles with disrupting neutrophil extracellular traps inhibit the progression of head and neck squamous cell carcinoma · 2026 · DOI

  • The relationship between mitochondrial fragmentation-induced mtDNA release and NET formation requires further clarification, particularly regarding vital NETosis mechanisms.

    Fumarate inhibits the formation of neutrophil extracellular traps (NETs) in a Nrf2-controlled and Annexin-A1-dependent manner associated with mitochondrial fusion · 2026 · DOI

  • The study does not clarify whether DMF promotes secretion of the 33-kDa ANXA1 species in neutrophils, as the canonical cleavage-dependent ANXA1 pathway differs from that observed in macrophages.

    Fumarate inhibits the formation of neutrophil extracellular traps (NETs) in a Nrf2-controlled and Annexin-A1-dependent manner associated with mitochondrial fusion · 2026 · DOI

  • Although their role as the first line of host defense is well established, their role in chronic granulomatous inflammations, diseases and infections remains poorly understood, and many questions on the activation, motility, bactericidity and termination of PMNL in these conditions remain unanswered.

    Neutrophil activation and periodontal tissue injury · 2015 · DOI

  • While complement components have been detected at low levels in genital tract fluids, including cervical mucus, the physiologic dynamics of complement in the female reproductive tract remain poorly characterized.

    Complement protein concentrations and activity in human cervical mucus · 2026 · DOI

  • Fraxinellone (FRA) inhibits Hypoxia-inducible factor-1α (HIF-1α) synthesis, but its binding mechanism and anti-APC action remain unclear.

    Fraxinellone mitigates acute lung injury by targeting HIF-1α to suppress pyroptosis and inflammation · 2026 · DOI

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