PUBLICATION
Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity
- Authors
- Liu, D., Zhou, C., Wang, X., Luo, Z., Xu, R., Huo, S., Guo, L., Luo, X., Yang, S., Click, A., Vancil, J., Barajas, P., Mijares, V., Baniasadi, H., Yan, N., Rehwinkel, J., Hancks, D.C., Chen, E.H., Liang, S., Zhong, Z.
- ID
- ZDB-PUB-260116-10
- Date
- 2026
- Source
- Science (New York, N.Y.) 391: eadq9006eadq9006 (Journal)
- Registered Authors
- Luo, Zhou
- Keywords
- none
- MeSH Terms
-
- Animals
- DNA, Mitochondrial/metabolism
- Fatty Liver/metabolism
- Humans
- Inflammasomes*/metabolism
- Insulin Resistance
- Interleukin-1beta/blood
- Interleukin-1beta/metabolism
- Macrophages/immunology
- Macrophages/metabolism
- Male
- Mice
- Mice, Inbred C57BL
- Mice, Knockout
- Mitochondria/metabolism
- NLR Family, Pyrin Domain-Containing 3 Protein*/metabolism
- Nucleotides*/metabolism
- Obesity*/genetics
- Obesity*/immunology
- Obesity*/metabolism
- SAM Domain and HD Domain-Containing Protein 1*/genetics
- SAM Domain and HD Domain-Containing Protein 1*/metabolism
- PubMed
- 41538457 Full text @ Science
Citation
Liu, D., Zhou, C., Wang, X., Luo, Z., Xu, R., Huo, S., Guo, L., Luo, X., Yang, S., Click, A., Vancil, J., Barajas, P., Mijares, V., Baniasadi, H., Yan, N., Rehwinkel, J., Hancks, D.C., Chen, E.H., Liang, S., Zhong, Z. (2026) Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity. Science (New York, N.Y.). 391:eadq9006eadq9006.
Abstract
Obesity is a major disease risk factor due to obesity-associated hyperinflammation. We found that obesity induced Nod-like receptor pyrin domain-containing 3 (NLRP3) inflammasome hyperactivation and excessive interleukin (IL)-1β production in macrophages by disrupting SAM and HD domain-containing protein 1 (SAMHD1), a deoxynucleoside triphosphate (dNTP) hydrolase crucial for nucleotide balance. This caused aberrant accumulation of dNTPs, which can be transported into mitochondria, and initiated mitochondrial DNA (mtDNA) neosynthesis, which increased the presence of oxidized mtDNA and triggered NLRP3 hyperactivation. Deletion of SAMHD1 promoted NLRP3 hyperactivation in cells isolated from zebrafish, mice, and humans. SAMHD1-deficient mice showed elevated circulating IL-1β, insulin resistance, and metabolic dysfunction-associated steatohepatitis. Blocking dNTP mitochondrial transport prevented NLRP3 hyperactivation in macrophages from obese patients and SAMHD1-deficient mice. Our study revealed that obesity by inhibiting SAMHD1 rewired macrophage nucleotide metabolism, thereby triggering NLRP3 inflammasome hyperactivation to drive disease progression.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping