GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE327nnn/GSE327348/primaryOK200TranscriptomicsHomo sapiensExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE327348GEOGSEfalseSphingomyelin d18:1/14:0 drives TLR4-dependent metaflammation [time course]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.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 sapiens