CEACAM1 Targets ABCA1 to mediate Atrial Fibrillation by regulating Lipophagy-Dependent Ferroptosis
Atrial fibrillation is one of the most common arrhythmias, imposing a significant burden on individuals due to its association with cerebrovascular events. The mechanisms underlying AF involve cardiac structural remodeling, electrical remodeling, and metabolic remodeling, with oxidative stress playing a crucial role. Our previous studies demonstrated that upregulation of CEACAM1 can increase oxidative stress, inhibit cell proliferation, and potentially contribute to cellular damage. As a unique form of regulated cell death, ferroptosis is characterized by oxidative stress and mitochondrial dysfunction induced by iron overload. In this study, we observed a significant increase in CEACAM1 expression in an AF model. Knocking out CEACAM1 revealed changes in mitochondrial membrane potential, reactive oxygen species (ROS) levels, intracellular Ca2+ concentration, channel proteins, and glycolipid metabolic enzymes. This knockout reversed electrical, structural, and metabolic remodeling in AF. Further investigation showed that CEACAM1 knockout inhibited ferroptosis, as evidenced by ferroptosis-related indicators. Using colocalization analyses of lipid droplets, lysosomes, and autophagosomes, we discovered that CEACAM1 knockout suppressed autophagy and lipophagy during AF. Supplementation with free fatty acids (FFAs) in the AF model post-CEACAM1 knockout suggested that the inhibition of ferroptosis was linked to a reduction in FFAs. Transcriptomic and non-targeted metabolomic analyses, along with ABCA1 interference studies, indicated that CEACAM1 knockout mitigates AF by promoting ABCA1 expression. In summary, CEACAM1 targets ABCA1 to mediate AF through the regulation of lipophagy-dependent ferroptosis, as demonstrated in both cellular and animal models.