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Background The pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD) remains unclear, and effective therapeutic strategies are lacking. The gut-liver axis plays a critical role in metabolic inflammation, but how myeloid cells regulate this interaction network through metabolites is poorly understood. This study aims to investigate the mechanism and therapeutic potential of myeloid Mas signaling in the gut-liver immunometabolic crosstalk in MASLD.Methods This study integrated multi-omics analyses from clinical cohorts of MASLD patients with myeloid-specific Mas1 deficiency mouse models. Techniques, including RNA sequencing, metabolomics, and single-cell transcriptomic analysis of intestinal and hepatic tissues, were employed to systematically elucidate the metabolite signaling axis mediated by myeloid Mas and its impact on parenchymal cell function.Results Myeloid Mas was identified as a critical regulator of gut-liver immunometabolic crosstalk. In macrophages, chenodeoxycholic acid (CDCA) activated Mas, recruited the transcriptional co-activator EP300, and inhibited FXR-driven transcription of EP300, thereby reducing Raptor acetylation, downregulating mTORC1 signaling, and decreasing spermidine synthesis. Disruption of this pathway led to reduced paracrine delivery of spermidine from macrophages to hepatocytes and intestinal epithelial cells, exacerbating hepatic steatosis and intestinal barrier dysfunction. Myeloid-specific Mas deficiency relieved this inhibition, allowing CDCA to activate FXR and restore the cascade to promote polyamine production. This protective crosstalk was primarily mediated by Mrc1 + macrophages through the THBS1-CD36 (liver) and TYROBP-CD44 (intestine) signaling axes. Clinical analyses revealed that spermidine levels were negatively correlated with MASLD severity. The FXR agonist Linafexor (CS0159) suppressed Mas expression and activated the polyamine synthesis pathway, significantly alleviating MASLD in mouse models.Conclusions This study reveals the key mechanism by which myeloid Mas regulates macrophage-epithelial crosstalk through the CDCA-FXR-EP300-Raptor-polyamine axis and demonstrates that myeloid-derived polyamines act as central mediators of gut-liver immunometabolic dialogue. Targeting this pathway, particularly through intervention with the FXR agonist CS0159, provides a novel therapeutic strategy and potential target for MASLD.