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The pathway map

Every research-blog post is tagged with one or more of the mechanistic categories used below (NLRP3, VDAC1, cGAS-STING, JAK-STAT, and so on). This page is the glossary: what each pathway is, and which of four color-coded streams it belongs to in the working disease model.

The same four streams drive the weekly literature screen β€” a paper is scored against this exact framework before it's added to the digest.

One root cause, four streams

SAMHD1 p.A565T leaves roughly 40–60% residual dNTPase activity, so the cytosolic dNTP pool β€” especially dGTP β€” runs high. That single upstream event branches into four largely independent streams, two of which converge on the NLRP3 inflammasome and two of which converge on type I interferon.

flowchart TD
    ROOT["<span style='color:#222'>SAMHD1 p.A565T<br/>dNTPase ↓40–60% β†’ cytosolic dNTP pool ↑</span>"]

    ROOT --> PURPLE["<span style='color:#fff'>🟣 PURPLE β€” dNTPase direct<br/>PNC1/PNC2 mito import β†’ POLG stalling</span>"]
    ROOT --> BLUE["<span style='color:#fff'>πŸ”΅ BLUE β€” mtDNA escape<br/>VDAC1 macropore loss β†’ cGAS–STING</span>"]
    ROOT --> GOLD["<span style='color:#332200'>🟑 GOLD β€” purine catabolism<br/>dGTP β†’ uric acid β†’ MSU crystals</span>"]

    PURPLE --> OXMTDNA["<span style='color:#222'>ox-mtDNA</span>"]
    OXMTDNA --> NLRP3["<span style='color:#222'>NLRP3 inflammasome<br/>IL-1Ξ² / IL-18</span>"]
    GOLD --> NLRP3

    BLUE --> IFN["<span style='color:#222'>Type I interferon (IFN-I)</span>"]
    IFN --> RED["<span style='color:#fff'>πŸ”΄ RED β€” IFN-I indirect<br/>JAK-STAT1/2 β†’ ISG15 β†’ mitophagy block</span>"]
    RED -.->|"more damaged mitochondria"| PURPLE

    classDef purple fill:#7700aa,stroke:#550088
    classDef blue fill:#003399,stroke:#002266
    classDef red fill:#c0000a,stroke:#900008
    classDef gold fill:#ddbb44,stroke:#aa9022
    classDef neutral fill:#eceff1,stroke:#90a4ae

    class PURPLE purple
    class BLUE blue
    class RED red
    class GOLD gold
    class ROOT,OXMTDNA,NLRP3,IFN neutral

Two parallel loops, not one sequence

NLRP3 and IFN-I are activated by two different molecular species escaping the mitochondrion in parallel, not one after the other: oxidized mtDNA (from stalled replication) feeds NLRP3, while unoxidized cytosolic mtDNA fragments (escaping through the VDAC1 macropore) feed cGAS-STING. Blocking one route does not shut down the other β€” which is the mechanistic argument for why a single drug class (e.g. a JAK inhibitor, which only addresses the IFN-I side) leaves a residual disease floor. See The Science for the clinical implications.

🟣 Purple stream β€” dNTPase direct

Blog categories: dNTPase, POLG-mtDNA, mito-dNTP-transport, nucleotide-rewiring

Excess cytosolic dGTP is imported into the mitochondrion through the PNC1/PNC2 nucleotide carriers (SLC25A33/SLC25A36), overwhelming the normal CMPK2-regulated salvage route. The resulting dNTP pool imbalance impairs POLG (mitochondrial DNA polymerase gamma) fidelity, producing strand breaks and oxidized mtDNA (ox-mtDNA) β€” a direct NLRP3 ligand.

Established: SAMHD1 loss and diet-independent obesity both drive this exact mitochondrial nucleotide-overload β†’ NLRP3 pathway, shown directly in SAMHD1-null and obese macrophages (Zhong et al., Science, 2026). Genetic knockdown of PNC1/PNC2, or the polymerase-gamma chain terminator ddC, blocks NLRP3 hyperactivation without correcting the underlying cytosolic dNTP overload β€” confirming mitochondrial dNTP import as the druggable step.

πŸ”΅ Blue stream β€” mtDNA escape / cGAS–STING bridge

Blog categories: VDAC1, cGAS-STING

SAMHD1 physically interacts with VDAC1 on the outer mitochondrial membrane. Losing that interaction opens the VDAC1 macropore, letting unoxidized (or mixed) cytosolic mtDNA fragments escape into the cytosol, where cGAS binds them and signals through cGAMP β†’ STING β†’ IRF3 to produce type I interferon.

Established: VBIT-4 (a VDAC1 oligomerization inhibitor) prevents cytosolic mtDNA release in SAMHD1-knockout monocytes and fully abolishes the spontaneous interferon-stimulated-gene response; IMSB301 (a cGAS inhibitor) normalizes the ISG signature in Aicardi–GoutiΓ¨res PBMCs β€” confirming this route is cGAS-dependent and VDAC1-gated, mechanistically distinct from the purple stream's NLRP3 route even though both start from the same damaged mitochondrion.

πŸ”΄ Red stream β€” IFN-I indirect

Blog categories: JAK-STAT, ISG15-mitophagy, IRF7-metabolic

Once type I interferon is running (from the blue stream), it drives sustained JAK-STAT1/2 signaling and ISG upregulation β€” including ISG15. ISGylation of MFN1/MFN2 blocks PINK1/Parkin-mediated mitophagy, and ISGylation of BECN1 blocks autophagic clearance by a second route, so damaged mitochondria pile up instead of being cleared. That, in turn, feeds back into the purple stream by generating more mitochondrial damage to react to.

This is the stream a JAK inhibitor directly addresses β€” clinically consistent with rapid symptom relief on a JAK inhibitor and relapse within 24–48 hours of stopping.

🟑 Gold stream β€” purine catabolism

Blog categories: NLRP3, urate-NLRP3

The same excess cytosolic dGTP that overloads mitochondrial import (purple stream) also has nowhere else to go: it's catabolized through the purine degradation pathway to uric acid, which can form monosodium urate (MSU) crystals in the cytosol β€” a second, independent NLRP3 activator. Because purple and gold both converge on NLRP3, a single upstream lesion drives the inflammasome from two directions at once.

Evidence strength

The dGTP β†’ urate β†’ MSU β†’ NLRP3 link is mechanistically consistent with established purine-catabolism and NLRP3-crystal biology, but has not yet been demonstrated directly in a SAMHD1 haploinsufficiency model β€” it is the least-confirmed of the four streams and is treated as a working hypothesis pending direct evidence.

Other categories used in the blog

A few tags don't map onto a single stream because they describe a cross-cutting axis or a translational angle rather than a step in the loop:

Category What it covers
NF-kB Priming and crosstalk that upregulates NLRP3/pro-IL-1Ξ² transcription upstream of both the purple and gold streams
mTOR-lysosomal Downstream lysosomal clearance failure feeding chronic inflammation
BIK-cancer SAMHD1's tumor-suppressor role, independent of the inflammatory loops above
AGS-spectrum, poliosis-neural-crest, pregnancy-fetal, ME-CFS Clinical phenotypes linked to chronic activation of the streams above, rather than mechanism steps themselves
gene-editing, treatment-target, clinical-phenotype Translational categories β€” therapeutic and diagnostic relevance rather than mechanism

This model synthesizes findings from multiple independently peer-reviewed papers into a single disease schema; no connection shown here is invented; the evidence strength for each link is called out explicitly above. It is a working research framework, not yet published as a peer-reviewed synthesis itself β€” see the research blog for how it evolves week to week as new evidence arrives.