Macrophage-derived KIF13B interacts with USP9X to attenuate abdominal aortic aneurysm development by potentiating TFEB stability

<b>Rationale:</b> Abdominal aortic aneurysm (AAA) is a highly lethal cardiovascular disorder for which there is no effective medication to date. Kinesin family member 13b (KIF13B), a vital motor protein, has been recently identified as a novel regulator of lipid metabolism. However, the role of KIF13B in AAA development has not been documented. <b>Methods:</b> We determined the expression of KIF13B in aortic tissues from clinical patients and porcine pancreatic elastase (PPE) or angiotensin II (ANG II)-induced AAA mouse models. To investigate the influence of KIF13B on AAA expansion, we established global, myeloid cell-specific and vascular smooth muscle cell (VSMC)-specific conditional <i>Kif13b</i>-deficient mice in PPE and/or ANG II-induced AAA models. <b>Results:</b> RNA-seq data from GEO database (GSE57691) revealed a significant decrease in <i>KIF13B</i> gene expression within the aortic tissues of patients with AAA. KIF13B protein levels were largely reduced in aortic tissue samples from patients and two mouse models with AAA. Complete inactivation of <i>Kif13b</i> or depleting <i>Kif13b</i> from myeloid cells but not smooth muscle cells (SMCs) exacerbated AAA development. Mechanistic studies identified transcription factor EB (TFEB) as a critical downstream target of KIF13B. KIF13B stabilized and upregulated TFEB by enhancing its deubiquitination through an interaction with deubiquitinase USP9X to maintain the proper function of lysosomes, thus inhibiting the senescence-associated secretory phenotype (SASP) and proinflammatory response of macrophages. Moreover, restoration of macrophage <i>Kif13b</i> or senolytic therapy dramatically mitigated AAA expansion <i>in vivo</i>. <b>Conclusions:</b> In the present study, we provided a new insight into the pathogenesis of AAA and defined a KIF13B-USP9X-TFEB axis that is essential for the regulation of macrophage function, suggesting that macrophage-derived <i>Kif13b</i> is a beneficial regulator of vascular homeostasis and targeting KIF13B could be a potential therapeutic approach for the treatment of human AAA disease in future clinical trial.