PAD4

PAD4 (Peptidylarginine Deiminase 4 / PADI4)

一行要約

好中球の核内 / 細胞質で発現するカルシウム依存性脱イミノ化酵素で、ヒストン H3 の Arg2/8/17 を citrulline へ変換する histone citrullination を介して chromatin decondensation を駆動し、Neutrophil-extracellular-traps (NET) 形成の起点酵素として機能する。GSK484 / Cl-amidine 等の小分子阻害剤で薬理学的に標的化可能であり、がん転移における NET-driven metastasis・血栓症・自己免疫疾患 (RA、SLE) の治療標的として注目される。

主要エビデンス

NET 形成の必須因子: PAD4 KO マウスは PMA / イオノマイシン / S. aureus 刺激下で NET 形成能が著しく低下し、citH3 (citrullinated histone H3) 陽性 NET を形成できない (Li et al., J Exp Med 2010)。Wang らの先行研究 (J Cell Biol 2009) で PADI4 が H3 citrullination による heterochromatin decondensation を駆動することが示され、NET 起点酵素としての位置づけが確立した。

がん転移における役割: Park ら (Sci Transl Med 2016) は乳癌肺転移モデルで neutrophil 由来 NET が dormant CTC を awakening させ、GSK484 による PAD4 阻害が転移を抑制することを示した。Albrengues et al. Science 2018 は炎症 / 喫煙誘発 NET が休眠 disseminated tumor cell を覚醒させる経路を laminin-integrin α3β1 シグナルで説明し、PAD4 阻害の治療的意義を裏付けた。

血栓症との関連: cancer-associated thrombosis (CAT) において circulating citH3 / MPO-DNA 複合体が血清 NET marker として上昇し、PAD4 が NETosis driven thrombosis (immunothrombosis) の central enzyme として機能する。

メカニズム

PAD4 はカルシウム結合により活性化し、ヒストン H3 / H4 の arginine 残基を citrulline へ変換 (脱イミノ化)。citrullinated histone は DNA との静電相互作用が弱まり chromatin decondensation を促進。並行して MPO (MPO) と neutrophil elastase (NE) が核に移行して chromatin processing に関与し、最終的に decondensed chromatin が好中球から細胞外に放出されて NET を形成する。CitH3 は血清 / 組織での NET formation の標準 marker として ELISA / IHC で測定される。

PAD4 inhibitor の薬理学的階層:

• GSK484: PAD4 選択的、低マイクロモル IC50、転移抑制マウスモデルで使用
• Cl-amidine / BB-Cl-amidine: PAD family 汎阻害、in vivo proof-of-concept 段階
• 臨床応用は前臨床段階、自己免疫 / がん補助療法として開発進行中

関連エンティティ・概念

• NET 形成カスケード共役因子: MPO (myeloperoxidase) / NE (neutrophil elastase) / HIF1A (hypoxia-driven NETosis)
• Concept: Neutrophil-extracellular-traps / NETosis-cancer-metastasis / Cancer-associated-thrombosis
• Pathway: NET formation pathway (histone citrullination → chromatin decondensation → DNA release)
• MOC: cancer-neutrophils

関連論文

直近 30 件のみ表示中 (関連 97 件)。 全件は MOC ページ または Obsidian (source Markdown) から辿れます。

Basic-Brain metastasis

• Cai et al. FrontImmunol 2026 — Mechanistic and functional characterization of NETsIL-17 as a therapeutic target in EMT and brain metastasis of lung
• Rabas et al. NatRevCancer 2024 — Cancer-induced systemic pre-conditioning of distant organs building a niche for metastatic cells
• Dunbar et al. TrendsCancer 2025 — Regulation of metastatic organotropism

Basic-Extracellular vesicles

• Zhang et al. CellRepMed 2026 — Artificial exosomes synergistically reshape sepsis immune homeostasis by modulating neutrophil fate and blocking
• Xie et al. IntImmunopharmacol 2025 — Neutrophil-derived exosomes promote sepsis-related multiple organ dysfunction through the induction of neutrophil
• Arya et al. NatCellBiol 2025 — Neutrophils secrete exosome-associated DNA to resolve sterile acute inflammation
• Ortmann et al. SciRep 2024 — Large extracellular vesicle (EV) and neutrophil extracellular trap (NET) interaction captured in vivo during systemic

Basic-Immunotherapy

• Pitter et al. JClinInvest 2025 — Citrullination in tumor immunity and therapy

Basic-Neutrophil and myeloid cell

• He et al. CancerCell 2024 — Chronic stress increases metastasis via neutrophil-mediated changes to the microenvironment
• Chen et al. CancerCell 2025 — DNASE1L3-expressing dendritic cells promote CD8+ T cell function and anti-PD-(l)1 therapy efficacy by degrading
• He et al. CancerCell 2025 — Chemotherapy awakens dormant cancer cells in lung by inducing neutrophil extracellular traps
• Lee et al. CancerCell 2025 — Neutrophil extracellular traps promote pre-metastatic niche formation in the omentum by expanding innate-like B cells
• Sturgeon et al. Cancers 2025 — Neutrophil dynamics contribute to disease progression and poor survival in pancreatic cancer
• Nemilostiva et al. ClinTranslOncol 2026 — CAR-engineered neutrophils derived from induced pluripotent stem cells a new frontier in cellular immunotherapy
• Zaranski et al. CommunBiol 2025 — NLRP3 inflammasome promotes PAD2 PAD4 release and protein citrullination in rheumatoid arthritis
• Yang et al. FrontImmunol 2025 — Unveiling cd177 a key player in tumors, autoimmune diseases, and inflammatory disorders
• McGarrity-Cottrell et al. FrontImmunol 2026 — Physiological, patho-physiological, and potential therapeutic roles for neutrophils in cancer & beyond
• Wu et al. FrontImmunol 2026 — Tumor-associated neutrophils in pancreatic ductal adenocarcinoma mechanisms and therapeutic targeting
• Baron et al. FrontOncol 2025 — Neutrophil extracellular traps are associated with poor response to neoadjuvant therapy and poor survival in pediatric
• Malavez-Cajigas et al. Heliyon 2024 — HL-60 cells as a valuable model to study LPS-induced neutrophil extracellular traps release
• Sun et al. Heliyon 2024 — Neutrophil extracellular trap genes predict immunotherapy response in gastric cancer
• Shahzad et al. NatRevCancer 2026 — Neutrophil extracellular traps in cancer
• Adrover et al. Nature 2025 — Neutrophils drive vascular occlusion, tumour necrosis and metastasis
• Burn et al. Nature 2025 — Myeloperoxidase transforms chromatin into neutrophil extracellular traps
• Liu et al. Neuron 2025 — Lcn2 from neutrophil extracellular traps induces astrogliosis and post-stroke emotional disorders
• Yu et al. Oncogene 2024 — Neutrophils in cancer dual roles through intercellular interactions
• Chen et al. SSRN 2024 — Circulating cell-in-cell tumor cells with neutrophils signature are hematogenous metastasis-initiating cells
• Zhou et al. SignalTransductTargetTher 2025 — Therapeutic potential of tumor-associated neutrophils dual role and phenotypic plasticity
• Xu et al. bioRxiv 2026 — Neutrophils repurpose the nucleolus as a cytokine reservoir and secretory organelle

Basic-Others

• Bojmar et al. NatMed 2024 — Multi-parametric atlas of the pre-metastatic liver for prediction of metastatic outcome in early-stage pancreatic cancer