2. Academic Validation
  3. Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity

Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity

  • Science. 2026 Jan 15;391(6782):eadq9006. doi: 10.1126/science.adq9006.
Danhui Liu 1,  Chuanli Zhou 1,  Xiaochen Wang 1,  Zhou Luo 2,  Ruiyao Xu 1,  Shanshan Huo 1,  Lina Guo 1,  Xuemei Luo 1,  Shuhan Yang 1,  Arielle Click 1,  Janiece Vancil 1,  Paola Barajas 1,  Victor Mijares 1,  Hamid Baniasadi 3,  Nan Yan 1,  Jan Rehwinkel 4,  Dustin C Hancks 1,  Elizabeth H Chen 2 5 6 7,  Shuang Liang 1 5,  Zhenyu Zhong 1 5
Affiliations

Affiliations

  • 1 Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 2 Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 3 Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 4 Medical Research Council Translational Immune Discovery Unit, Medical Research Council Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, University of Oxford, Oxford, UK.
  • 5 Harold C. Simmons Comprehensive Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 6 Department of Cell Biology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
  • 7 Hamon Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
PMID: 41538457 DOI: 10.1126/science.adq9006
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.

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