Peripheral arterial disease (PAD) represents a formidable healthcare challenge, particularly in the context of global population aging. This condition exerts substantial impact on quality of life and overall health outcomes across societies worldwide (Shamaki et al., 2022). Epidemiological data from China illustrates the magnitude of this burden, with approximately 6.6 % of individuals over 35 years of age (representing 45.3 million people) affected by PAD-associated conditions. Among elderly populations (≥60 years), prevalence rates escalate significantly, ranging from 2.8 % to 15.3 % (Gao et al., 2021). Advanced age functions as an independent contributor to vascular system dysregulation, with increasing chronological age correlating with diminished angiogenic capacity (Ueno et al., 2023). Vascular endothelial cells (ECs) serve as the critical interface between circulating blood and vessel walls, facilitating bidirectional transport of nutrients and bioactive compounds. These specialized cells maintain vascular homeostasis through multiple mechanisms, including regulation of vasomotor tone and promotion of vessel remodeling and growth (Trimm and Red-Horse, 2023). Their functional integrity is therefore central to cardiovascular health.

The metabolic end-product uric acid derives from xanthine through enzymatic conversion by xanthine oxidase or xanthine dehydrogenase, with subsequent urinary elimination (Gherghina et al., 2022). Under physiologic conditions, uric acid circulates as soluble urate with tightly regulated synthesis and excretion maintaining homeostatic balance. However, this equilibrium can be disrupted by excessive dietary purine consumption, metabolic abnormalities, or enzymatic dysfunction, resulting in elevated serum uric acid concentrations (Wen et al., 2024). When levels exceed 408 μmol/L, sodium urate may crystallize, precipitating gouty arthritis, particularly within joint spaces. The prevalence of hyperuricemia has shown marked growth in recent decades, with established associations between this metabolic disorder and gout (Dalbeth et al., 2021; Yanai et al., 2021). Importantly, the pathophysiological consequences of hyperuricemia extend beyond crystal-mediated effects. As reported previously, patients with gout have a significantly increased risk of cardiovascular diseases. The underlying mechanism lies in the systemic damage caused by sodium urate to the vascular endothelial function (Tie et al., 2024). Sodium urate crystals can deposit on the vessel walls, directly damaging the endothelium through mechanisms such as oxidative stress, inflammatory activation and smooth muscle proliferation (Ubhadiya et al., 2023). Consequently, elucidating the molecular pathways through which uric acid impairs endothelial function represents a critical step toward developing targeted interventions for PAD.

The endoplasmic reticulum (ER) stress response constitutes a mechanistic link between endothelial dysfunction and subcellular homeostasis disruption (Ouyang et al., 2022). As the primary site for protein synthesis and folding, the ER responds to various physiological and pathological stimuli that promote accumulation of misfolded or unfolded proteins within its lumen, triggering adaptive signaling networks (Celik et al., 2023). The unfolded protein response (UPR) initially attempts to restore ER homeostasis by attenuating protein synthesis, enhancing protein folding capacity, and promoting degradation of misfolded proteins (Wiseman et al., 2022). Failure to reestablish ER equilibrium results in sustained stress response activation, precipitating diverse cellular dysfunctions (Hetz et al., 2020). Recent scientific interest has focused intensively on uric acid's role in ER stress induction across multiple cell types. Yan and colleagues (Yan et al., 2018) demonstrated that uric acid promotes cardiomyocyte apoptosis through Calpain-1 activation and subsequent ER stress. Similarly, Choi et al. (Choi et al., 2014) established that uric acid stimulates hepatic lipid accumulation by triggering ER stress through SREBP-1c activation.

Sphingomyelin synthase 2 (SMS2), as a key enzyme in sphingomyelin biosynthesis, is mainly located in the cell membrane and the Golgi membrane system (Ou et al., 2021). Its core function is to catalyze the exchange of the head groups of ceramide and phosphatidylcholine to generate sphingomyelin and release diacylglycerol (Jiang et al., 2024). It has been reported that SMS2 promotes endothelial dysfunction by inducing ER stress (Hua et al., 2019). However, the relationship between SMS2 and uric acid-mediated ER stress and resultant endothelial dysfunction is not clear.

Our investigation sought to characterize the mechanisms underlying uric acid-mediated ER stress and resultant endothelial dysfunction. This research aims to provide novel mechanistic insights and establish foundational knowledge for developing therapeutic strategies targeting vascular complications in hyperuricemic states.