Abdominal aortic aneurysm (AAA) exerts a profound influence on cardiovascular homeostasis via inflammation-driven pathological alterations and intramural bleeding events, which impair the structural integrity of vascular walls and elevate the risk of fatal rupture in affected individuals. In this research, oxidized hemoglobin (Hb), particularly the ferrylHb (Fe4+) subtype, was detected in the peripheral circulation of patients suffering from ruptured AAA. This finding signifies the systemic spread of oxidative stress-derived byproducts, which correlate closely with the severity of the disease. The present study was designed to pinpoint the origin of Hb oxidation that leads to ferrylHb production, both in human AAA lesions complicated by hemorrhage and in an experimental AAA model induced by angiotensin II (AngII) in apolipoprotein E-deficient (ApoE-/-) mice. Simultaneously, the research aimed to clarify the metabolic fate of ferrylHb and its corresponding pathophysiological impacts. FerrylHb formation was confirmed within hemorrhagic AAA tissues obtained from human subjects. This process was characterized by the oxidative modification of three specific cysteine residues-βCys93, αCys104 and βCys112-located on the globin chains of Hb. Concomitantly, covalently bonded globin dimers, tetramers and higher order multimers were generated; these oligomeric complexes represent the end products of interactions between Hb, neutrophils and macrophages within the pathologically altered arterial wall. Notably, the AngII-induced AAA model in ApoE-/- mice recapitulated these key pathological features of human AAA, exhibiting prominent vascular wall hemorrhagic transformation and robust ferrylHb synthesis. Employing a newly generated monoclonal antibody targeting ferrylHb for immunohistochemical assays, the study demonstrated that extracellular ferrylHb is internalized by neutrophils through a CD163 receptor-mediated endocytic pathway, thereby triggering granulocyte activation in the aortic wall microenvironment. Upon ferrylHb uptake, neutrophils exhibited enhanced transcriptional activity skewed toward a proinflammatory phenotype. Specifically, genes associated with chemotactic signaling, cytokine biosynthesis and macrophage recruitment were markedly upregulated. Sustained exposure to ferrylHb triggered neutrophil degranulation, resulting in the release of elastase and myeloperoxidase. These proteolytic enzymes accelerate elastin degradation, which in turn contributes to the structural weakening of the aortic wall. Moreover, ferrylHb stimulation promoted the formation of neutrophil extracellular traps, a process that fosters a local microenvironment characterized by heightened inflammation and thrombogenic potential within the aneurysmal tissue. Transcriptomic profiling via RNA sequencing was performed on human AAA tissues, with healthy aortic tissues serving as controls. The analysis identified 4,327 differentially expressed genes (DEGs), among which 2,473 genes were significantly upregulated and 1,854 genes were downregulated. Functional annotation of these DEGs revealed strong associations with biological processes including neutrophil activation, inflammatory response, iron metabolic regulation, vascular calcification and cellular apoptosis. Gene ontology enrichment analysis further highlighted three core biological processes: neutrophil chemotaxis, neutrophil migration and neutrophil aggregation, which collectively underscore the pivotal role of neutrophils in the pathophysiological progression of AAA. Notably, ruptured human AAA tissues displayed a distinct transcriptomic signature, with 43% of DEGs overlapping with those identified in human macrophages exposed to ferrylHb in vitro. Within this set of 884 overlapping genes, functional clusters related to inflammatory modulation, angiogenic signaling and tissue remodeling were identified. Mechanistic investigations conducted on endothelial cells and vascular smooth muscle cells revealed that heme exposure induces the expression of interleukin-1β (IL-1β), intercellular adhesion molecule 1 (ICAM1) and NLR family pyrin domain containing 3 (NLRP3). This proinflammatory response was attenuated by the upregulation of heme oxygenase-1 (HO-1). Pharmacological induction of HO-1 using Normosang exerted a protective effect, mitigating aneurysm progression and suppressing local inflammation. In contrast, inhibition of HO-1 activity exacerbated disease severity. These results identify the heme-HO-1-H-ferritin signaling axis as a key regulatory module in AAA pathogenesis and a promising candidate for therapeutic targeting. In summary, the present study elucidates that the crosstalk between oxidized Hb and neutrophils and macrophages within the aortic wall microenvironment plays an active role in driving ferrylHb generation, immune cell activation and extracellular matrix degradation-all of which are critical processes that promote AAA progression. Furthermore, the detection of ferrylHb in the circulation of patients with ruptured AAA highlights its potential utility as a diagnostic biomarker for evaluating disease activity and stratifying rupture risk. These mechanistic insights provide a rational basis for developing targeted therapies that interfere with the Hb-neutrophil-macrophage axis, with the goal of alleviating inflammation and proteolytic damage in AAA and opening new avenues for clinical intervention.