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Preprint WatchMildOctober 2nd, 2026

Extracellular cGAMP transmission exacerbates neuroinflammation in aging and multiple sclerosis

R. Carvalho, D.; Wang, R.; Liu, N.; Li, Y.; Younis, T.; Sclip, A.; Shin, S.; Pawluk, A.; Goodarzi, H.; Thaiss, C.; Konermann, S.; Li, L.

ENPP1 is the dominant cGAMP hydrolase in brain and spinal cord and acts as a protective brake on STING-dependent neuroinflammation. It is reported as downregulated in experimental autoimmune encephalomyelitis mice and in multiple sclerosis patients, and mice lacking cGAMP hydrolysis activity showed worse EAE paralysis and premature aging phenotypes, leading the authors to nominate CNS ENPP1 enhancement as a therapeutic strategy.

Mild contradiction

1 prior failure

One documented clinical failure (Phase 1 or 2) overlaps with the claimed mechanism.

The therapeutic direction proposed here, raising ENPP1 activity, matches the direction of the only ENPP1 programme in the Claidex graph, where recombinant ENPP1 replacement reached phase 3 and stopped on biomarker grounds (inz-701-enpp1-gaci-energy-2-phase3-biomarker-failure). That recorded failure concerns endpoint and biomarker selection in a monogenic calcification disease rather than the catalytic hypothesis, so it does not contradict this neuroinflammation proposal. It does carry a warning that transfers directly. An ENPP1-enhancing CNS programme would face the same question the ENERGY programme met, which is whether a tractable pharmacodynamic marker tracks the clinical endpoint closely enough to support a registrational design. Here that marker would have to report on extracellular cGAMP or downstream interferon-stimulated gene induction inside the central nervous system, which is a harder sampling problem than plasma pyrophosphate was.

Abstract excerpt

Neuroinflammation drives neurodegeneration and cognitive decline in aging, but the signals that spread this inflammation across the CNS remain unclear. Here, we show in mice that advanced age and experimental autoimmune encephalomyelitis (EAE) both result in elevated cytosolic mtDNA in microglia, which stimulates the production and export of cGAMP from these cells. Meanwhile, ENPP1, the dominant cGAMP hydrolase in the brain and spinal cord, is downregulated in both EAE mice and MS patients, releasing the brake on extracellular cGAMP accumulation. In Enpp1H362A mice, which selectively lack cGAMP hydrolysis activity, unrestrained extracellular cGAMP worsens EAE-associated paralysis and drives premature aging phenotypes including impaired motor coordination (rotarod, pole test) and reduced exploration (open field test) in a manner dependent on STING. Single-cell RNA sequencing pinpoints microglia, astrocytes, and inhibitory neurons as the principal cGAMP responders that activate STING-dependent interferon-stimulated gene induction in response to elevated extracellular cGAMP. Mechanistically, microglia import cGAMP through the LRRC8A:C channel, while astrocytes and neurons import cGAMP via the glutamate antiporter system xc-, reinforced by SLC1A2-mediated glutamate uptake in astrocytes and SLC38A1/2-fueled glutamine-to-glutamate synthesis in neurons. In isolated primary astrocytes and neurons, high intracellular glutamate and system xc--driven redox demands favor cGAMP uptake, raising the possibility that neurotransmitter cycling and redox burden shape cellular vulnerability to cGAMP immunotransmission in vivo. Together, these findings position ENPP1 as a protective brake on neuroinflammation in aging and MS, nominating cGAS inhibition and CNS ENPP1 enhancement as therapeutic strategies.

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This is an automated contradiction flag, not an editorial judgment on the preprint's quality. Flags identify where the preclinical literature and the clinical failure record diverge.