{"database":"GEO","file_versions":[{"headers":{"Content-Type":["application/json"]},"body":{"files":{"Other":["ftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE325nnn/GSE325520/"]},"type":"primary"},"statusCode":"OK","statusCodeValue":200}],"scores":null,"additional":{"omics_type":["Transcriptomics"],"species":["Homo sapiens"],"gds_type":["Expression profiling by high throughput sequencing"],"full_dataset_link":["https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE325520"],"repository":["GEO"],"entry_type":["GSE"],"additional_accession":[]},"is_claimable":false,"name":"Sphingomyelin d18:1/14:0 drives TLR4-dependent metaflammation [SM14]","description":"Chronic low-grade inflammation, or metaflammation, is a hallmark of common non-communicable diseases. Here we identified short chain sphingomyelins as key endogenous triggers connecting nutrient excess to innate immune activation. Using atherosclerosis as a discovery model, we performed an unbiased in vivo screen integrating thousands of systemic inflammatory and metabolic measurements using supervised machine-learning analysis and identified sphingomyelin d18:1/14:0 (SM14) as a prominent disease-associated feature. SM14 directly ligates the Toll-Like Receptor 4 (TLR4) – Myeloid Differentiation Factor 2 (MD-2) (TLR4–MD-2) complex and induced a differentiation-sensitive, pro-inflammatory signalling programme. Unlike canonical TLR4 signalling induced by lipopolysaccharide (LPS), SM14 elicited a distinct signalling cascade and failed in mounting a robust interferon response at physiological concentrations. Human intervention and disease cohorts showed that circulating SM14 is diet-responsive, increased in cardiovascular and metabolic disease, and present at concentrations sufficient to activate immune cells in vitro. These findings identify SM14 as a physiologically regulated endogenous TLR4 ligand and suggest that species-resolved lipid remodelling can sustain biased innate immune signalling in chronic inflammatory disease.","dates":{"publication":"2026/09/09"},"accession":"GSE325520","cross_references":{"GSM":["GSM9605617","GSM9605616","GSM9605615","GSM9605614"],"GPL":["30173"],"GSE":["325520"],"taxon":["Homo sapiens"]}}