Abstract
Abdominal aortic aneurysm (AAA) rupture remains a fatal vascular event with limited mechanistic understanding beyond diameter-based risk assessment. Emerging evidence suggests that metabolic reprogramming contributes to aneurysm progression, yet regulators linking metabolism to rupture remain poorly defined. An AngII/BAPN-induced mouse model generated intact (iAAA) and ruptured AAA (rAAA) tissues. Bulk RNA sequencing and untargeted metabolomics profiled transcriptomic and metabolic alterations across sham, iAAA, and rAAA groups. Candidate ubiquitin-specific proteases (USPs) were screened by integrated transcriptomic analysis. Functional studies in human aortic smooth muscle cells (HASMCs) used USP53 knockdown and overexpression. Glycolytic activity was evaluated by glucose uptake, lactate production, ATP levels, and related gene/protein expression. In vivo relevance was assessed using AAV-mediated USP53 silencing in the AAA model. Transcriptomic analysis revealed inflammatory and immune activation during AAA formation, but limited gene changes distinguished rAAA from iAAA tissues. Metabolomic profiling demonstrated metabolic divergence among groups, with ruptured aneurysms showing enrichment of nucleotide metabolism, cAMP/cGMP signaling, energy pathways. Integration analysis identified USP53 as a deubiquitinase upregulated during AAA development and rupture. In HASMCs, USP53 promoted glycolytic metabolism, increased glucose transporter expression, lactate production, reduced oxidative phosphorylation markers. In vivo, USP53 knockdown attenuated vascular remodeling, reduced proliferative activity, partially normalized metabolic disturbances in aneurysmal tissues.AAA rupture is associated with distinct metabolic remodeling beyond inflammatory gene activation. USP53 functions as a previously unrecognized regulator of vascular metabolic reprogramming, promoting glycolysis and contributing to aneurysm progression. Targeting USP53 may represent a potential strategy to mitigate AAA instability and rupture risk.