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CEACAM1 Targets ABCA1 to mediate Atrial Fibrillation by regulating Lipophagy-Dependent Ferroptosis

ABSTRACT:

Atrial fibrillation（AF） 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.

INSTRUMENT(S): Liquid Chromatography MS - negative - reverse phase, Liquid Chromatography MS - positive - reverse phase

PROVIDER: MTBLS13308 | MetaboLights | 2025-11-12

REPOSITORIES: MetaboLights

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			Action	DRS
	a_MTBLS13308_LC-MS_negative_reverse-phase_metabolite_profiling.txt	Txt
	a_MTBLS13308_LC-MS_positive_reverse-phase_metabolite_profiling.txt	Txt
	i_Investigation.txt	Txt
	m_MTBLS13308_LC-MS_negative_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular
	m_MTBLS13308_LC-MS_positive_reverse-phase_metabolite_profiling_v2_maf.tsv	Tabular

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Project description:Sepsis-associated acute kidney injury (SA-AKI) is a critical condition characterized by high morbidity and mortality rates, particularly in intensive care settings. This study focuses on RP105, a pattern recognition receptor, exploring its role in moderating the mechanisms of oxidative stress and ferroptosis during SA-AKI, offering insights into its potential as a therapeutic target. SA-AKI model was established using RP105 knockout (KO) and wild-type (WT) mice through cecal ligation and puncture (CLP). Comprehensive evaluations included the assessment of ferroptosis markers and the expression levels of pro-inflammatory cytokines. RP105 expression was markedly reduced in the kidneys following CLP induction, correlating with worsened renal outcomes. Compared to the Sham group, RP105-/- mice displayed heightened renal damage, increased levels of oxidative stress markers, and enhanced lipid peroxidation. Notably, the deficiency of RP105 led to increased macrophage infiltration and a shift towards pro-inflammatory phenotypes, which further potentiated ferroptosis and exacerbated renal tissue damage. By influencing macrophage behavior and mitigating inflammatory responses. RP105 deficiency exacerbates macrophage-induced inflammation, oxidative stress, and ferroptosis, forming a vicious cycle that leads to more severe renal injury. These findings underscore the pivotal role of RP105 in mitigating oxidative stress and suppressing ferroptosis in the context of SA-AKI through regulation of the HO-1/SLC7A11/GPX4 axis. By preventing macrophage polarization toward a pro-inflammatory phenotype, RP105 alleviates inflammatory responses and tissue damage, highlighting its potential as a therapeutic target. In contrast, RP105 deficiency exacerbates macrophage-driven inflammation, oxidative stress, and ferroptosis, creating a vicious cycle that worsens kidney injury. Thus, RP105 emerges as a promising therapeutic candidate for mitigating sepsis-induced renal damage.

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CEACAM1 Targets ABCA1 to mediate Atrial Fibrillation by regulating Lipophagy-Dependent Ferroptosis

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