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.