Targeting the PI3K/Akt/NF‐κB axis: Cluster of differentiation 5‐like‐mediated immunometabolic regulation of macrophage polarization in abdominal aortic aneurysm

Abdominal aortic aneurysm (AAA) is a life‐threatening vascular disorder lacking effective pharmacological interventions. We identified CD5 molecule‐like (CD5L) as a regulator of macrophage polarization in AAA via the phosphoinositide 3‐kinase/protein kinase B/nuclear factor kappa B (PI3K/Akt/NF‐κB) pathway. Transcriptomic analyses (GSE47472 and GSE57691) and angiotensin II (AngII)‐infused apolipoprotein E‐deficient (ApoE −/− ) mice showed CD5L upregulation, inversely correlated with M1 macrophage infiltration. In vitro CD5L overexpression reduced, whereas knockdown increased M1 polarization and pro‐inflammatory cytokines in RAW264.7 cells and human monocyte‐derived macrophages. In vivo, CD5L knockdown aggravated aortic dilation, vascular disruption, and inflammatory mediator expression. Pharmacological modulation confirmed PI3K/Akt as essential for CD5L's anti‐inflammatory action: LY294002 amplified, whereas PI3K activator 740Y‐P mitigated CD5L deficiency effects. RNA sequencing confirmed PI3K/Akt activation downstream of CD5L. These results define CD5L as an immunometabolic checkpoint that suppresses NF‐κB‐mediated inflammation, suggesting a therapeutic target for AAA.