circ_0043837 attenuates macrophage mitochondrial damage through XPO1-associated HuR transport in atherosclerosis

Macrophage mitochondrial damage is implicated in the pathogenesis of atherosclerosis. Circular RNAs (circRNAs) regulate mitochondrial energy metabolism and contribute to the development of various diseases, but the mechanism in atherosclerosis regulation remains to be elucidated. This study aimed to investigate the underlying mechanisms by which circRNAs modulate mitochondrial function in the progression of atherosclerosis. We established a macrophage-derived foam cell model to define the role of circ_0043837 in mitochondrial dysfunction during atherosclerosis. Foam cells showed loss of mitochondrial membrane potential, mtDNA fragmentation, reduced mitochondrial transcription factor A (TFAM) expression and impaired nuclear export of the RNA-binding protein HuR. Upregulation of circRNA (circ_0043837) exerted a protective effect on mitochondrial membrane potential and restored regular HuR nuclear export. RNA pull-down, mass spectrometry and immunofluorescence identified the nuclear export receptor XPO1 as a circ_0043837-interacting protein, through which circ_0043837 regulated HuR trafficking. In vivo, exosome-mediated delivery of circ_0043837 delayed carotid atherosclerotic plaque progression in mice. Together, our study demonstrated that circ_0043837 plays a protective role against atherosclerosis by interacting with XPO1, regulating HuR nuclear export and attenuating macrophage mitochondrial damage.