Atherosclerosis is a chronic cardiovascular disease characterized by the accumulation of fibrous plaques in arterial walls. This process is driven by dysregulated cholesterol/lipid metabolism and inflammation, where oxidized low-density lipoprotein (oxLDL) particles infiltrate the arterial intima, triggering inflammatory responses and foam cell formation [1,2]. Foam cells, lipid-laden macrophages and vascular smooth muscle cells (VSMCs), are hallmarks of early lesions and represent critical therapeutic targets for slowing disease progression [3].

VSMCs are crucial in atherosclerosis, exhibiting high phenotypic plasticity and functional complexity [4]. Under physiological conditions, contractile VSMCs regulate vascular tone and blood flow. However, during atherosclerosis, VSMCs undergo phenotypic switching to a synthetic state, characterized by increased expression of synthetic markers and decreased contractile proteins. This phenotypic switch enables VSMCs to proliferate, migrate to the intima, and convert into foam cells, contributing significantly to plaque formation and instability [5]. Additionally, VSMCs can differentiate into osteoblast-like cells, promoting vascular calcification, which is a key contributor to plaque instability [6]. Critically, VSMC death mediated by apoptosis, necroptosis, or other regulated pathways, driven by inflammatory, oxidative, and biomechanical stressors, exacerbates plaque vulnerability and can trigger plaque rupture, a major complication of atherosclerosis [7,8].

O-GlcNAcylation is a dynamic and reversible post-translational modification involving the attachment of O-linked β-N-acetylglucosamine (O-GlcNAc) to serine/threonine residues of nuclear, cytoplasmic, and mitochondrial proteins [9,10]. This essential modification serves as a crucial nutrient and stress sensor that regulates diverse cellular processes including transcription, signaling, and metabolic homeostasis [11,12]. The cycling of O-GlcNAc is catalyzed by two antagonistic enzymes: O-GlcNAc transferase (OGT), which adds the modification, and O-GlcNAcase (OGA), which removes it [13]. The hexosamine biosynthetic pathway generates the donor substrate UDP-GlcNAc, linking O-GlcNAcylation to cellular metabolic status [14]. O-GlcNAc modification exhibits extensive crosstalk with other post-translational modifications, particularly phosphorylation, and participates in a sophisticated regulatory network that modulates protein function and stability [15,16]. As a key metabolic sensor, O-GlcNAcylation plays complex roles in regulating multiple programmed cell death pathways [17]. Emerging evidence demonstrates its involvement in apoptosis, necroptosis, pyroptosis, and ferroptosis through mechanisms involving mitochondrial dysfunction, ER stress, oxidative stress, and specific death pathway activation [[18], [19], [20]]. Both elevated and deficient states of O-GlcNAcylation have been linked to cell death, highlighting its critical role in maintaining cellular homeostasis under stress conditions [21,22].

PANoptosis, a newly defined proinflammatory programmed cell death (PCD) pathway, emerges from crosstalk between pyroptosis, apoptosis, and necroptosis. Triggered by specific stimuli and coordinated by PANoptosome complexes, it exhibits features of all three death pathways but cannot be fully explained by any single one [23,24]. PANoptosis contributes to infection, cancer, and inflammatory diseases, yet its role in VSMCs and atherosclerosis is unexplored [25].

Emerging evidence links O-GlcNAcylation to vascular pathology through its regulation of VSMC phenotypic switching and vascular calcification in diseases such as atherosclerosis and chronic kidney disease [26]. Our prior work demonstrated that OGT-mediated O-GlcNAcylation promotes high phosphate-induced vascular calcification by modifying β-catenin [27]. Recent studies further show OGT regulates vascular calcification through VSMC autophagy, while O-GlcNAcylation of AKT enhances RUNX2-driven calcification in diabetes [[28], [29], [30]]. Notably, smooth muscle cell (SMC)-specific Ogt deletion attenuates atherosclerosis in hyperglycemic Apoe−/− mice, yet the mechanisms underlying OGT's regulation of VSMC-derived foam cell formation remain unclear [31].

In this study, we observed significant downregulation of OGT-mediated O-GlcNAcylation during VSMC-to-foam cell transition. Using Apoe−/− mice with SMC-specific Ogt knockout (Apoe−/−SM22ΔOgt), we demonstrate that OGT deficiency enhances lipid accumulation in foam cells yet paradoxically reduces atherosclerotic plaque size under hyperglycemic conditions induced by high-fat/high-cholesterol diet (HFHCD) and streptozotocin (STZ). Mechanistically, our data suggest that Ogt deletion reduces plaque burden through augmented PANoptosis in VSMC-derived foam cells within atherosclerotic lesions. These findings establish O-GlcNAc signaling as a critical regulator of VSMC homeostasis and identify PANoptosis as a pivotal mechanism limiting atherosclerosis progression.