Metabolic pathways and cell death modalities in diabetic complications: unraveling pyroptosis, ferroptosis, cuproptosis, and disulfidptosis

The pathogenesis of diabetic complications involves a complex interplay of metabolic disturbances, in which diverse programmed cell death (PCD) pathways play a pivotal role. This article systematically reviews the molecular mechanisms of four novel types of metabolic cell death-pyroptosis, ferroptosis, cuproptosis and disulfidptosis-with a focus on their specific pathological roles in diabetic kidney disease, retinopathy, cardiovascular complications and neuropathy. It also analyzes the crosstalk and synergistic regulatory networks among these four cell death modalities. Studies have demonstrated that in the diabetic microenvironment, these four PCD pathways do not act independently; instead, they form an interconnected regulatory network centered on oxidative stress, inflammatory signaling and metal ion homeostasis imbalance. This network collectively amplifies metabolic stress, inflammatory responses and oxidative damage, thereby accelerating the progression of multi-organ injury in diabetes. Furthermore, this article explores the therapeutic implications of this network-based perspective, highlighting the potential value of multi-target intervention strategies in the treatment of diabetic complications. In summary, this review clarifies the intricate associations between metabolic cell death pathways and diabetic complications, and underscores the importance of the crosstalk among different cell death modalities. It thus provides a novel theoretical framework for understanding the systemic pathophysiological mechanisms of diabetes, and offers insights and directions for the development of novel combination therapeutic strategies.