Nucleotide metabolic rewiring enables NLRP3 inflammasome hyperactivation in obesity

• 成果类型: Article
• 署名作者: Liu, Danhui; Zhou, Chuanli; Wang, Xiaochen; Luo, Zhou; Xu, Ruiyao; Huo, Shanshan; Guo, Lina; Luo, Xuemei; Yang, Shuhan; Click, Arielle; Vancil, Janiece; Barajas, Paola; Mijares, Victor; Baniasadi, Hamid; Yan, Nan; Rehwinkel, Jan; Hancks, Dustin C.; Chen, Elizabeth H.; Liang, Shuang; Zhong, Zhenyu
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Oxford; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; Hebei Agricultural University
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adq9006
• 发表日期: 2026-01-15
• 页码: eadq9006
• 关键词: IN-VITRO SUPPLEMENTATION; mitochondrial-dna; immune-responses; innate immunity; cell-cycle; samhd1; activation; RESTRICTION; phosphorylation; inhibition

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)-1 beta 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-1 beta, 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.