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The Role and Mechanism of the cGAS-STING/NLRP3 Signaling Axis-Regulated p38 MAPK/NF-κB Pathway in Manganese-Induced

Shiyin Zhong1, Qiongli Zhou1, Jirui Yang1

  • 1Department of Toxicology, School of Public Health, Lanzhou University, Lanzhou 730000, China.

Environment & Health (Washington, D.C.)
|May 21, 2026
PubMed

Insights

Manganese overexposure triggers neurotoxicity by activating the cGAS-STING/NLRP3 axis, which is regulated by the p38 MAPK/NF-κB pathway, leading to pathological Tau aggregation and Parkinson

Area of Science:

  • Neuroscience
  • Toxicology
  • Molecular Biology

Background:

  • Manganese (Mn) is essential but elevated environmental levels cause neurotoxicity.
  • Chronic Mn overexposure leads to Parkinson's-like symptoms, with unclear mechanisms.
  • Pathological Tau aggregation is a hallmark of neurodegenerative diseases.

Purpose of the Study:

  • Investigate the role of the cGAS-STING/NLRP3 axis in Mn-induced neurotoxicity.
  • Elucidate the regulation of the p38 MAPK/NF-κB pathway in Mn-induced Tau aggregation.
  • Determine the link between cGAS-STING/NLRP3, p38 MAPK/NF-κB, and Tau pathology.

Main Methods:

  • Utilized in vitro and in vivo models for Mn exposure studies.
  • Employed genetic ablation of cGAS, STING, and NLRP3.
  • Performed RNA-sequencing and pharmacological inhibition of p38 MAPK and NF-κB.

Main Results:

  • MnCl2 exposure activated cGAS-STING/NLRP3 and p38 MAPK/NF-κB pathways, increasing Tau expression.
  • Genetic ablation of cGAS, STING, or NLRP3 attenuated Mn-induced Tau upregulation.
  • Inhibition of p38 MAPK/NF-κB reduced cGAS-STING signaling, inflammation, and phosphorylated Tau (p-Tau).

Conclusions:

  • The cGAS-STING/NLRP3 axis mediates Mn-induced Tau expression via the p38 MAPK/NF-κB pathway.
  • Mn exposure activates cGAS-STING/NLRP3, which is regulated by p38 MAPK/NF-κB, driving Tau aggregation.
  • This pathway represents a potential therapeutic target for Mn-induced neurotoxicity.
Keywords:
cGAS−STING/NLRP3 signaling axisinducing pathological tau aggregationmanganeseneuroinflammationp38 MAPK/NF–κB pathwaytau aggregation

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