Necroptosis is a regulated form of cell death characterized by receptor-interacting protein kinase (RIPK) activation, leading to necrosome formation and subsequent membrane rupture. Increasing evidence indicates that necroptosis contributes to metabolic syndrome (MetS) by promoting tissue inflammation, insulin resistance, and metabolic dysfunction. The molecular mechanisms underlying necroptosis in MetS primarily involve activation of the RIPK1-RIPK3-MLKL axis, particularly in metabolically active tissues such as skeletal muscle, liver, adipose tissue, and pancreatic β-cells. Although numerous experimental studies have linked necroptosis to metabolic inflammation and organ injury, a systematic synthesis of its mechanistic roles, biomarker relevance, and translational potential in MetS remains limited. This review summarizes current evidence on the molecular regulation of necroptosis in MetS, its involvement in disease progression across multiple organs, and emerging diagnostic, prognostic, and theragnostic biomarkers. In addition, this review discusses therapeutic strategies targeting necroptosis and critically evaluates their translational challenges. By integrating mechanistic and translational perspectives, this review aims to provide a balanced framework for understanding the role of necroptosis in MetS and to highlight key knowledge gaps that warrant further investigation.

Proper development of the heart during the fetal period is a prerequisite for health in later life. It was shown that maternal supplementation with stilbenoid resveratrol (RES) is beneficial for cardiovascular function. Synthetic glucocorticoid dexamethasone (DEX) is commonly used in the prenatal treatment of respiratory distress syndrome. RES affects the circadian clock in various tissues but its effect on the fetal heart has not been studied. We hypothetized that RES may affect the the circadian clock via modulation of the glucocorticoid signaling and/or mitochondrial function. Therefore, we tested the effects of different concentrations of RES and synthetic glucocorticoid dexamethasone (DEX) on the circadian clock, energy metabolism and mitochondrial function in fetal cardiomyocytes (CMCs) and cardiac fibroblasts (FBs). We found that RES affects the clock in both CMCs and FBs by increasing the stability of the clock protein PER2. In CMCs, the effect was mediated via the adenylyl cyclase signaling pathway. RES modulated DEX-induced effects on the circadian clock in CMCs and FBs. We were able to detect a circadian rhythm in mitochondrial function in fetal heart cells, which was confirmed by ATP and resazurin assays as well as visualization of the mitochondrial network and reactive oxygen species (ROS). Interestingly, we found that both drugs shifted the phase of fetal heart clock, but had no effect on the phase of mitochondrial rhythmicity, indicating a possible uncoupling of circadian and mitochondrial rhythms in fetal CMCs and FBs. Overall, our data revealed fetal heart-specific effects of RES on the circadian clock through the stabilization of PER2 protein and its ability to modulate DEX-induced effects on the clock.