[Corilagin reduces macrophage-derived foam cell formation by regulating endoplasmic reticulum stress-autophagy]

This study aimed to investigate the effect of corilagin(Cor) on the formation of foam cells derived from J774A.1 macrophages and to explore its underlying mechanism based on the endoplasmic reticulum stress(ERS)-endoplasmic reticulum autophagy(ER-phagy) pathway. J774A.1 macrophages were used as the research model and divided into the control group, oxidized low-density lipoprotein(ox-LDL) group, tunicamycin(TM) group, and Cor treatment groups with different concentrations. Cell proliferation activity was assessed using the MTT assay. Intracellular lipid droplet accumulation was observed by oil red O staining. The levels of total cholesterol(TC) and free cholesterol(FC) in cells, as well as interleukin-6(IL-6) and monocyte chemoattractant protein-1(MCP-1) in the cell supernatants, were measured using enzyme-linked immunosorbent assay(ELISA). Intracellular reactive oxygen species(ROS) levels and apoptosis were analyzed by flow cytometry. The interaction between Cor and the eukaryotic translation initiation factor 2α(eIF2α) target protein was predicted by molecular docking. The expression levels of ERS-and autophagy-related proteins were detected by Western blot. The results showed that, compared with the model group, Cor dose-dependently reduced intracellular lipid droplets. The cholesterol ester(CE)/TC ratio was significantly decreased in the low-, medium-, and high-dose Cor groups, indicating reduced lipid deposition. In the high-dose Cor group, the levels of inflammatory cytokines IL-6 and MCP-1 in the supernatant were significantly reduced. In addition, intracellular ROS levels and apoptosis rates were markedly decreased. The optimal binding affinity between Cor and eIF2α was-8.4 kcal·mol~(-1). Furthermore, the high-dose Cor significantly downregulated the expression levels of phosphorylated(p)-eIF2α/eIF2α, activating transcription factor 4(ATF4), glucose-regulated protein 78(GRP78), C/EBP homologous protein(CHOP), nuclear factor-κB(NF-κB), Bcl-2-associated X protein(Bax), and testis expressed gene 264(Tex264), while upregulating the expression level of B-cell lymphoma-2(Bcl-2). In conclusion, Cor inhibits the formation of macrophage-derived foam cells by regulating the expression of proteins in the eIF2α-ATF4-Tex264 signaling pathway, thereby suppressing ERS-induced excessive ER-phagy and apoptosis in macrophages.