SPI1-Mediated Metabolic Reprogramming in Neuroinflammation

Mechanistic description

SPI1 transcriptionally coordinates both inflammatory gene expression and metabolic enzymes in activated microglia, shifting cells toward glycolytic metabolism that sustains chronic neuroinflammation. Metabolic modulators targeting SPI1-regulated enzymes could restore homeostatic microglial metabolism.

Mechanism / pathway

SPI1
→
neuroinflammation

Evidence for (5)

Microglial phagocytosis in Alzheimer disease.

PMID:41315858 2026 Nat Rev Neurol
Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment.

PMID:34526055 2021 Mol Neurodegener
Spi1 aggravates neuropathic pain by modulating Clec7a-mediated neuroinflammation and microglial phagocytosis.

PMID:40640733 2025 J Headache Pain
Pu.1/Spi1 dosage controls the turnover and maintenance of microglia in zebrafish and mammals.

PMID:40673490 2025 Elife
Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC.

PMID:40494892 2025 Nat Commun

Evidence against (3)

Microglial phagocytosis in Alzheimer disease.

PMID:41315858 2026 Nat Rev Neurol
Alzheimer's Disease Genetics: A Dampened Microglial Response?

PMID:34142603 2023 Neuroscientist
Late onset Alzheimer's disease genetics implicates microglial pathways in disease risk.

PMID:28549481 2017 Mol Neurodegener

Evidence matrix

5 supporting 3 contradicting

63% supporting

Supporting

Microglial phagocytosis in Alzheimer disease. PMID:41315858 · 2026 · Nat Rev Neurol
Adult-onset CNS myelin sulfatide deficiency is sufficient to cause Alzheimer's disease-like neuroinflammation and cognitive impairment. PMID:34526055 · 2021 · Mol Neurodegener
Spi1 aggravates neuropathic pain by modulating Clec7a-mediated neuroinflammation and microglial phagocytosis. PMID:40640733 · 2025 · J Headache Pain
Pu.1/Spi1 dosage controls the turnover and maintenance of microglia in zebrafish and mammals. PMID:40673490 · 2025 · Elife
Iterative transcription factor screening enables rapid generation of microglia-like cells from human iPSC. PMID:40494892 · 2025 · Nat Commun

Contradicting

Microglial phagocytosis in Alzheimer disease. PMID:41315858 · 2026 · Nat Rev Neurol
Alzheimer's Disease Genetics: A Dampened Microglial Response? PMID:34142603 · 2023 · Neuroscientist
Late onset Alzheimer's disease genetics implicates microglial pathways in disease risk. PMID:28549481 · 2017 · Mol Neurodegener

Cite this hypothesis

Citation

etl-backfill (2026). SPI1-Mediated Metabolic Reprogramming in Neuroinflammation. SciDEX hypothesis. https://prism.scidex.ai/hypotheses/hyp-SDA-2026-04-08-gap-pubmed-20260406-062122-bfac06c8-1

BibTeX

@misc{scidex_hypothesis_hypsda20,
  title        = {SPI1-Mediated Metabolic Reprogramming in Neuroinflammation},
  author       = {etl-backfill},
  year         = {2026},
  howpublished = {SciDEX hypothesis},
  url          = {https://prism.scidex.ai/hypotheses/hyp-SDA-2026-04-08-gap-pubmed-20260406-062122-bfac06c8-1},
  note         = {SciDEX artifact hypothesis:hyp-SDA-2026-04-08-gap-pubmed-20260406-062122-bfac06c8-1}
}