Hypothesis Comparison

graph TD
    A["Amyloid-beta plaques
and inflammatory signals"] --> B["Microglial activation
to DAM phenotype"]
    B --> C["ACSL4 gene
transcriptional upregulation"]
    C --> D["ACSL4 protein
enzymatic activity increase"]
    D --> E["Arachidonic acid esterification
to arachidonyl-CoA"]
    D --> F["Adrenic acid esterification
to adrenoyl-CoA"]
    E --> G["PE-AA synthesis
in membrane phospholipids"]
    F --> H["PE-AdA synthesis
in membrane phospholipids"]
    G --> I["PUFA-PE membrane
substrate accumulation"]
    H --> I
    B --> J["GPX4 downregulation
and GSH depletion"]
    I --> K["Ferroptotic priming
state establishment"]
    J --> K
    L["Iron accumulation
in brain tissue"] --> M["Fenton reaction
hydroxyl radical generation"]
    M --> N["Lipid peroxidation
of PUFA-PE substrates"]
    K --> N
    N --> O["Membrane integrity
disruption and damage"]
    O --> P["Microglial ferroptotic
cell death execution"]
    P --> Q["Pro-inflammatory
mediator release"]
    P --> R["Reduced phagocytic
clearance capacity"]
    Q --> S["Neuroinflammation
amplification"]
    R --> T["Amyloid plaque
accumulation"]
    S --> U["Neuronal dysfunction
and cognitive decline"]
    T --> U

    classDef normal fill:#4fc3f7,stroke:#2196f3
    classDef therapeutic fill:#81c784,stroke:#4caf50
    classDef pathology fill:#ef5350,stroke:#f44336
    classDef outcome fill:#ffd54f,stroke:#ff9800
    classDef molecular fill:#ce93d8,stroke:#9c27b0

    class A,L pathology
    class B,C,D,E,F,G,H,I,J,M,N normal
    class K,O,P molecular
    class Q,R,S,T outcome
    class U pathology

graph TD
    A["Microglial Activation
TREM2-dependent"] --> B["ACSL4 Upregulation"]
    B --> C["AA/AdA Esterification
into PE Phospholipids"]
    C --> D["PUFA-PE Membrane
Enrichment 3-5x"]

    E["Disease State"] --> F["GPX4 Downregulation"]
    E --> G["xCT/SLC7A11 Reduction"]
    G --> H["GSH Depletion"]
    F --> I["Loss of Lipid
Peroxide Defense"]
    H --> I

    J["Iron Accumulation
TFRC up / FTH1 saturated"] --> K["Labile Fe2+ Pool"]
    K --> L["Fenton Chemistry
OH Radical Generation"]

    D --> M["Ferroptotic Priming"]
    I --> M
    L --> M

    M --> N["Lipid Peroxidation
Cascade"]
    N --> O["Microglial Ferroptosis"]
    O --> P["DAMP Release
4-HNE, MDA, oxPL"]
    O --> Q["Iron Release"]
    P --> R["Neuroinflammation
Amplification"]
    Q --> K
    R --> A

    style M fill:#ff6b6b,stroke:#c92a2a,color:#fff
    style O fill:#ff8787,stroke:#c92a2a,color:#fff
    style B fill:#ffd43b,stroke:#f08c00,color:#000
    style F fill:#ffd43b,stroke:#f08c00,color:#000
    style K fill:#ffa94d,stroke:#e8590c,color:#000