Year: 2026
Type: article
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.
Source: Science
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funders: Cancer Prevention and Research Institute of Texas, University of Texas Southwestern Medical Center, National Institutes of Health, National Institute of General Medical Sciences, National Institute of Allergy and Infectious Diseases, National Institute of Arthritis and Musculoskeletal and Skin Diseases
Awards: Role ofCMPK2 in Liver Inflammation and Hepatocellular Carcinoma, Role of IRF1 in NLRP3 inflammasome activation and inflammatory diseases, Investigating the mechanism of NLRP3 inflammasome hyperactivation during hepatocellular carcinoma development, Sting Trafficking and Signaling Beyond Interferon, Investigating mechanisms of vertebrate myoblast fusion using zebrafish as a model, Recruitment of First-Time, Tenure-Track Faculty Members, Restoring TREM2-Depedent Efferocytosis to Inhibit Obesity-Induced Liver Inflammation and Cancer Development, G9000016835, G9000062875, G9000099380, G9000178381, Evolution-guided Studies of Mitochondrial Functions
OpenAlex ID: W7124314767