GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE325nnn/GSE325520/primary200OKTranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE325520GEOGSEfalseSphingomyelin d18:1/14:0 drives TLR4-dependent metaflammation [SM14]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.2026/09/09GSE325520GSM9605617GSM9605616GSM9605615GSM960561430173325520Homo sapiens