Nrf2 modulates macrophage foam cells senescence and autophagy activation

Foam cell formation is a critical pathological process that contributes significantly to the development of atherosclerosis, influenced by processes such as vascular senescence and autophagy-lysosomal pathways. The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has recently received interest due to its role in foam cell formation, but its connection to senescence and autophagy are still not well defined. This research investigated the role of Nrf2 in modulating senescence and autophagy in foam cells using an <i>in vitro</i> model of THP-1-derived macrophage foam cells. The effect of siRNA-induced silencing of Nrf2 on intracellular lipids buildup, cholesterol efflux, and the activation of senescence and autophagy were analyzed. Our findings indicate that Nrf2 silencing reduced the formation of foam cells by lowering intracellular lipid accumulation and enhancing cholesterol efflux in THP-1 macrophages. Additionally, silencing of Nrf2 lead to a reduction in cellular senescence, reflected by reduced β-galactosidase activity and a decrease in the expression of senescence-associated secretory phenotype (SASP) markers (Matrix metalloproteinase-9 (MMP-9) and tumor necrosis factor (TNF-α)) expression. This is accompanied by activation of autophagy, as indicated by enhanced formation of autophagosome and LC3B expression. Furthermore, inhibiting the late stage of autophagy with hydroxychloroquine (HCQ) decreased cell viability, while early-stage autophagy inhibition using 3-Methyladenine (3-MA) had no significant effect. These results highlight the critical role of Nrf2 in controlling foam cell development, senescence, and autophagic processes, giving valuable insights into potential therapeutic targets for atherosclerosis.