Elevated CERS6/C16:0 Ceramide in taPVAT Promotes Aortic Dissection by Driving Macrophage Inflammation via FPR2/NF-κB Signaling

BACKGROUND: Perivascular adipose tissue (PVAT) is the endocrine microenvironment closest to the aorta. Using multiomics analysis, we found that Cers6 (ceramide synthase 6) was upregulated and C16:0 ceramide accumulated in thoracic aortic PVAT (taPVAT) from aortic dissection (AD) mice; however, its role and underlying mechanism in AD remain unclear. METHODS: A mouse model of AD was established by combined β-aminopropionitrile and AngII (angiotensin II) administration, followed by proteomic and quantitative lipidomic analyses of taPVAT. Cers6 expression in taPVAT adipocytes was locally manipulated by adeno-associated virus delivery, and exogenous C16:0 ceramide was administered in vivo. Mechanistic studies were performed using adipocyte–bone marrow–derived macrophage (BMDM) coculture and C16:0 ceramide-stimulated BMDMs, combined with transcriptomics, pharmacological inhibition, molecular docking, surface plasmon resonance, cellular thermal shift assay, and small interfering RNA knockdown. WRW4 intervention was evaluated in vivo. Human taPVAT samples were used to validate CERS6/C16:0 ceramide changes and clinical correlations. RESULTS: Cers6 was selectively upregulated in taPVAT from AD mice, accompanied by increased C16:0 ceramide levels. Specific knockdown of Cers6 in taPVAT adipocytes reduced AD incidence and attenuated aortic ECM (extracellular matrix) degradation and inflammation, whereas Cers6 overexpression or exogenous C16:0 ceramide aggravated disease. In vitro, Cers6/C16:0 ceramide enhanced macrophage inflammatory activation, migration, and Mmp9 (matrix metalloproteinase-9) expression via Fpr2 (formyl peptide receptor 2)/NF-κB (nuclear factor-κB) signaling. WRW4 mitigated these pro-AD effects in vivo. Similarly, in human taPVAT, CERS6 and C16:0 ceramide were elevated, and C16:0 ceramide correlated positively with aortic inflammatory gene expression and maximal thoracic aortic diameter. CONCLUSIONS: taPVAT Cers6-driven C16:0 ceramide accumulation promotes AD through macrophage Fpr2/NF-κB signaling, enhancing inflammation and ECM degradation. Targeting taPVAT Cers6 or blocking the Fpr2/NF-κB axis may offer a tissue-focused therapeutic strategy.