过度活跃
炎症体
核苷酸
细胞生物学
吡喃结构域
生物
线粒体
化学
SAMHD1公司
效应器
下调和上调
分泌物
受体
胞浆
生物化学
端粒
促炎细胞因子
三磷酸腺苷
炎症
基因沉默
切梅林
巨噬细胞
HEK 293细胞
白细胞介素6
分子生物学
胰岛素
基因敲除
焊剂(冶金)
半胱氨酸蛋白酶1
作者
Danhui Liu,Chuanli Zhou,Xiaochen Wang,Zhou Luo,Ruiyao Xu,Shanshan Huo,Lina Guo,Xuemei Luo,Shuhan Yang,Arielle Click,Janiece Vancil,Paola Barajas,Victor Mijares,Hamid Baniasadi,Nan Yan,Jan Rehwinkel,Dustin C. Hancks,Elizabeth H. Chen,Shuang Liang,Zhenyu Zhong
出处
期刊:Science
[American Association for the Advancement of Science]
日期:2026-01-15
卷期号:391 (6782): eadq9006-eadq9006
被引量:5
标识
DOI:10.1126/science.adq9006
摘要
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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