Diabetes mellitus, a metabolic disorder characterized by high morbidity, is associated with complications that significantly impact both quality of life and overall health [1]. Vascular calcification (VC), a crucial pathological mechanism underlying cardiovascular events, involves the deposition of hydroxyapatite within the walls of blood vessels [2]. The presence of elevated glucose levels has been shown to enhance the incidence of VC [3]. Furthermore, individuals with diabetes mellitus experience an accelerated progression of VC, ultimately leading to the development of cardiovascular diseases [[4], [5], [6], [7]]. The primary factor contributing to calcification, a phenotypic transformation from vascular smooth muscle cells (VSMCs) to osteoblast-like cells, is likely the lack of immune cells, specifically macrophages [8]. Extensive prior research has consistently shown that VSMC calcification typically arises in high glucose environments, with Bone morphogenetic protein-2 (BMP-2) potentially serving as a crucial indicator of the osteoblastic phenotype [[9], [10], [11]]. Therefore, suppressing the dysfunctions of VSMCs, including calcification, abnormal proliferation and migration, may offer a potential intervention target for hyperglycemia-related vascular diseases.

Post-translational modifications (PTMs) play a crucial role in regulating protein function and integrating metabolic processes with physiology or pathology [12]. While many studies have focused on the regulatory mechanisms of common PTMs such as phosphorylation, methylation, and acetylation, recent research has uncovered a novel PTM called succinylation. Succinylation involves the modification of protein lysine groups through metabolically derived succinyl CoA [13,14]. The dependence of succinylation on succinyl-CoA formed in the tricarboxylic acid (TCA) cycle has been elucidated through succinylated quantitative analysis [15]. In the majority of instances, intracellular succinyl-CoA is primarily derived from alpha-ketoglutaric acid, succinylcarnitine, and succinic acid within the mitochondrial TCA cycle. Additionally, the transportation of carnitine during the fatty acid beta-oxidation process contributes to an elevation in the concentration of succinyl-CoA [16]. These two processes are intricately linked to the aberrations observed in glucose and lipid metabolism in individuals with diabetes mellitus. The disruption in glucose aerobic oxidation metabolism resulting from elevated glucose levels and diabetes can lead to an increase in succinyl-CoA levels, thereby playing a role in the progression of diabetes. Succinyl-CoA has the ability to traverse the mitochondrial membrane, resulting in the production of Ksucc (lysine succinylation modification) in both cytoplasmic proteins and nuclear histones. In addition to its involvement in cancer, succinylation has been found to play a crucial role in other diseases, including hypertrophic cardiomyopathy and ischemia of the heart and brain [17,18]. Various classical post-translational modifications (PTMs), such as acetylation (Histone acetyl transferases) and deacetylases (HDAC inhibitors), have been extensively studied and have led to the development of drugs for manipulation [19]. However, the field of succinylation or de-succinylation is still in its early stages, as the fundamental mechanisms underlying these processes remain obscure. Given the promising application in prevention and treatment of diabetes mellitus, more investigations based on specific molecular mechanism need to be initiated.

The compound known as 12,13-dihydroxy-9Z-octadecenoic acid (12,13-diHOME) has been identified as a lipokine and functions as a ligand for the peroxisome proliferator-activated receptor γ (PPAR-γ). The production of 12,13-diHOME occurs through the actions of epoxide hydrolase and epoxygenase during the metabolism of linoleic fatty acid (C18:2 ω6). Recent studies have indicated that 12,13-diHOME plays a significant role in blood glucose homeostasis, the metabolic balance of fatty acids, glucose metabolism, and the production of metabolic heat in brown adipose tissue. The ingestion of fatty acids in brown adipose tissue can be enhanced, leading to improved glucose and fatty acid metabolism. Additionally, it has significant implications for cardiopulmonary function, as well as immune and inflammatory responses [23]. Recent studies have provided evidence that 12,13-diHOME derived from brown adipose tissue (BAT) can enhance cardiac function and cardiomyocyte respiration in heart failure patients by modulating type 1 nitric oxide synthase (NOS1) [24]. In this study, the potential effects of 12,13-diHOME on various physiological processes, such as fatty acid uptake in BAT and skeletal muscle, BAT energy consumption, metabolism improvement, and cardiac function enhancement in heart failure patients, were investigated [25]. These findings suggest that 12,13-diHOME may significantly mitigate the risk of arteriosclerosis. However, the specific influence of 12,13-diHOME on vascular calcification under high glucose conditions remains uncertain. Therefore, this research aims to elucidate the regulatory mechanism of 12,13-diHOME in the promotion of VSMC calcification induced by elevated glucose levels.