Metabolic dysfunction-associated steatohepatitis (MASH) is driven by immune-mediated hepatic inflammation, triggered in part by lipid dysregulation, especially elevated palmitic acid, which activates the sphingolipid pathway and raises sphingosine 1-phosphate (S1P) levels. S1P acts through five G-protein-coupled receptors (S1P1–5) to promote proinflammatory responses. Previous studies showed that pharmacologic S1P inhibition reduces liver inflammation. This study used a myeloid cell–specific S1P1 knockout mouse model (S1pr1MKO) to clarify S1P1’s role in MASH. Despite similar steatosis and body mass, S1pr1MKO mice on a high-fat, high-fructose, high-cholesterol diet exhibited significantly less liver inflammation, injury, and fibrosis compared to wild-type controls.

S1P1 deletion in myeloid cells reduced hepatic accumulation of pro-inflammatory monocyte-derived macrophages (MDMs), increased restorative resident macrophages, and suppressed inflammatory gene expression. Mass cytometry and transcriptomics confirmed enhanced apoptosis in S1P1-deficient macrophages, suggesting impaired survival as a key mechanism. Unlike prior studies using non-specific S1P inhibitors, this targeted approach isolates myeloid S1P1 as a critical driver of MASH inflammation. These findings support macrophage-specific S1P1 as a therapeutic target for reducing liver injury and fibrosis in MASH without altering steatosis.

Reference: Parthasarathy G, Venkatesan N, Sidhu GS, et al. Deletion of sphingosine 1-phosphate receptor 1 in myeloid cells reduces hepatic inflammatory macrophages and attenuates MASH. Hepatol Commun. 2025 Feb 3;9(2):e0613. doi: 10.1097/HC9.0000000000000613. PMID: 39899672.