GEOapplication/xmlftp://ftp.ncbi.nlm.nih.gov/geo/series/GSE304nnn/GSE304787/primary200OKTranscriptomicsMus musculusExpression profiling by high throughput sequencinghttps://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE304787GEOGSEfalseTherapeutic targeting of lipidated amino acid deficiency ameliorates MASH via a PPARα/CCL2 axisMetabolic dysfunction-associated steatohepatitis (MASH), affects nearly one-third of the global population with limited pharmacotherapy approved, underscoring the urgent need for new therapeutic strategies. N-acyl amino acids (NAAs), comprising amino acids linked to long-chain fatty acid acyl groups, are gaining interest, yet their metabolic regulation in MASH remains elusive. Metabolomic profiling in mice and humans with MASH revealed a marked depletion of NAAs, particularly C18:1-Leu, which inversely correlated with disease severity. The bidirectional PM20D1 expression was suppressed in the livers of human and mice with MASH, as well as in lipid-loaded primary mouse hepatocytes and hepatic cell lines. Stable isotope tracing studies in mice with and without MASH confirmed reduced biosynthesis of C18:1-Leu. Genetically, hepatocyte-specific overexpression of PM20D1 or pharmacological treatment with exogenous C18:1-Leu significantly attenuated or reversed established MASH. Mechanistically, C18:1-Leu bound and activated peroxisome proliferator-activated receptor alpha (PPARα), enhancing fatty acid β-oxidation and suppressing the NF-κB/CCL2 axis, thereby reducing hepatic macrophage infiltration, inflammation, and fibrosis. These therapeutic effects were abolished in hepatocyte-specific PPARα- and CCL2-deficient mice, identifying C18:1-Leu as a promising metabolic therapy for MASH.2026/07/01GSE304787GSM9157290GSM9157291GSM9157300GSM9157289GSM9157301GSM9157298GSM9157288GSM9157299GSM9157296GSM9157297GSM9157294GSM9157295GSM9157292GSM915729315103304787Mus musculus