{"title":"己糖激酶2在脓毒症诱导的小胶质细胞中促进酰基辅酶a合成酶长链家族成员4的isgyylation。","authors":"Guangyang Bai, Shun Ke, Jun Lu, Shanshan Yu, Shusheng Li, Minghao Fang, Jianmin Ling","doi":"10.1016/j.jlr.2025.100776","DOIUrl":null,"url":null,"abstract":"<p><p>Metabolic reprogramming is often observed in sepsis-associated microglial cells. However, little is known about the aberrant metabolic genes involved in neuroinflammation and lipid accumulation in microglial cells of sepsis-associated encephalopathy (SAE). Here, we show that hexokinase 2 (HK2) is upregulated and strongly associated with the inflammatory response and lipid metabolism in lipopolysaccharide-induced BV2 cells. Downregulation of HK2 lowered the activation of NOD-like receptor signaling family pyrin domain containing 3, both in BV2 cells and in the hippocampus of cecal ligation and puncture-induced male septic mice. Moreover, the inhibition of HK2 promoted lipid droplet reduction. Mechanistically, HK2 knockdown in microglial cells reduced the ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4) by interferon-stimulated gene 15 (ISG15). Notably, siISG15 effectively down-regulated the expression of ACSL4 in lipopolysaccharide-induced BV2 cells. Our findings provide new mechanistic insights into HK2 in microglial cells through regulation of ACSL4 ISGylation, suggesting a promising therapeutic strategy for treating SAE by targeting HK2. Our findings suggest that HK2 modulates ISGylation of ACSL4 in sepsis-induced microglial cells, indicating that therapeutic targeting of HK2 may constitute a promising strategy for SAE.</p>","PeriodicalId":16209,"journal":{"name":"Journal of Lipid Research","volume":" ","pages":"100776"},"PeriodicalIF":5.0000,"publicationDate":"2025-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12018552/pdf/","citationCount":"0","resultStr":"{\"title\":\"Hexokinase 2 promotes ISGylation of Acyl-CoA synthetase long-chain family member 4 in sepsis-induced microglia cells.\",\"authors\":\"Guangyang Bai, Shun Ke, Jun Lu, Shanshan Yu, Shusheng Li, Minghao Fang, Jianmin Ling\",\"doi\":\"10.1016/j.jlr.2025.100776\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>Metabolic reprogramming is often observed in sepsis-associated microglial cells. However, little is known about the aberrant metabolic genes involved in neuroinflammation and lipid accumulation in microglial cells of sepsis-associated encephalopathy (SAE). Here, we show that hexokinase 2 (HK2) is upregulated and strongly associated with the inflammatory response and lipid metabolism in lipopolysaccharide-induced BV2 cells. Downregulation of HK2 lowered the activation of NOD-like receptor signaling family pyrin domain containing 3, both in BV2 cells and in the hippocampus of cecal ligation and puncture-induced male septic mice. Moreover, the inhibition of HK2 promoted lipid droplet reduction. Mechanistically, HK2 knockdown in microglial cells reduced the ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4) by interferon-stimulated gene 15 (ISG15). Notably, siISG15 effectively down-regulated the expression of ACSL4 in lipopolysaccharide-induced BV2 cells. Our findings provide new mechanistic insights into HK2 in microglial cells through regulation of ACSL4 ISGylation, suggesting a promising therapeutic strategy for treating SAE by targeting HK2. Our findings suggest that HK2 modulates ISGylation of ACSL4 in sepsis-induced microglial cells, indicating that therapeutic targeting of HK2 may constitute a promising strategy for SAE.</p>\",\"PeriodicalId\":16209,\"journal\":{\"name\":\"Journal of Lipid Research\",\"volume\":\" \",\"pages\":\"100776\"},\"PeriodicalIF\":5.0000,\"publicationDate\":\"2025-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12018552/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Lipid Research\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.1016/j.jlr.2025.100776\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/3/12 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Lipid Research","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1016/j.jlr.2025.100776","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/3/12 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
Hexokinase 2 promotes ISGylation of Acyl-CoA synthetase long-chain family member 4 in sepsis-induced microglia cells.
Metabolic reprogramming is often observed in sepsis-associated microglial cells. However, little is known about the aberrant metabolic genes involved in neuroinflammation and lipid accumulation in microglial cells of sepsis-associated encephalopathy (SAE). Here, we show that hexokinase 2 (HK2) is upregulated and strongly associated with the inflammatory response and lipid metabolism in lipopolysaccharide-induced BV2 cells. Downregulation of HK2 lowered the activation of NOD-like receptor signaling family pyrin domain containing 3, both in BV2 cells and in the hippocampus of cecal ligation and puncture-induced male septic mice. Moreover, the inhibition of HK2 promoted lipid droplet reduction. Mechanistically, HK2 knockdown in microglial cells reduced the ISGylation of Acyl-CoA Synthetase Long-chain Family Member 4 (ACSL4) by interferon-stimulated gene 15 (ISG15). Notably, siISG15 effectively down-regulated the expression of ACSL4 in lipopolysaccharide-induced BV2 cells. Our findings provide new mechanistic insights into HK2 in microglial cells through regulation of ACSL4 ISGylation, suggesting a promising therapeutic strategy for treating SAE by targeting HK2. Our findings suggest that HK2 modulates ISGylation of ACSL4 in sepsis-induced microglial cells, indicating that therapeutic targeting of HK2 may constitute a promising strategy for SAE.
期刊介绍:
The Journal of Lipid Research (JLR) publishes original articles and reviews in the broadly defined area of biological lipids. We encourage the submission of manuscripts relating to lipids, including those addressing problems in biochemistry, molecular biology, structural biology, cell biology, genetics, molecular medicine, clinical medicine and metabolism. Major criteria for acceptance of articles are new insights into mechanisms of lipid function and metabolism and/or genes regulating lipid metabolism along with sound primary experimental data. Interpretation of the data is the authors’ responsibility, and speculation should be labeled as such. Manuscripts that provide new ways of purifying, identifying and quantifying lipids are invited for the Methods section of the Journal. JLR encourages contributions from investigators in all countries, but articles must be submitted in clear and concise English.