Abstract Body: Introduction：Calcific aortic valve disease (CAVD) is characterized by lipid deposition and inflammatory macrophage infiltration, yet the molecular mechanisms linking lipid metabolism to valvular calcification remain unclear.
Hypothesis：This study investigates the role of Sam68, an RNA-binding protein, in Methods ：macrophage lipid homeostasis and its contribution to CAVD progression.Using an ApoE-/- mouse model of aortic valve calcification and human calcified aortic valves, we analyzed Sam68 expression via immunohistochemistry and single-cell RNA sequencing (scRNA-seq). Macrophage subsets were characterized, and lipid metabolism pathways were assessed through functional assays (ox-LDL uptake, cholesterol efflux, lipophagy).
Results ：Sam68 was upregulated in calcified valves, co-localizing with scar-associated macrophages (SAMs) and pro-inflammatory subsets (M1, Birc5+). scRNA-seq revealed Sam68 enrichment in pathways related to autophagy and lipid metabolism. Sam68 knockout enhanced lipid phagocytosis, reduced scavenger receptor (SR-A1/CD36/LOX-1) activation, and decreased ox-LDL uptake, thereby suppressing foam cell formation. It also promoted lysosomal-lipid droplet fusion (lipophagy) and reduced intracellular cholesterol ester accumulation.
Conclusions：Sam68 exacerbates CAVD by impairing macrophage lipid clearance and promoting pro-inflammatory macrophage polarization. Targeting Sam68 may restore lipid homeostasis and mitigate valvular calcification, offering a novel therapeutic strategy for CAVD.