Programmed cell death in kidney disease: integrated crosstalk among ferroptosis, pyroptosis, apoptosis, and cuproptosis.

Programmed cell death (PCD) is a central determinant of kidney injury, maladaptive repair, and chronic progression. Beyond classical apoptosis, the identification of ferroptosis, pyroptosis, and cuproptosis has expanded the conceptual framework of renal pathophysiology by linking cell fate decisions to redox imbalance, inflammatory signaling, mitochondrial metabolism, and metal ion homeostasis. Ferroptosis is driven by iron-dependent phospholipid peroxidation and impaired antioxidant defenses; pyroptosis is mediated by inflammasome activation, gasdermin pore formation, and cytokine release; apoptosis results from caspase-dependent cellular dismantling; and cuproptosis reflects copper-induced disruption of lipoylated tricarboxylic acid cycle proteins and mitochondrial proteostasis. Here, we propose a "metabolic crisis-cascade" framework, in which progressive disruption of energy metabolism, redox balance, and metal homeostasis acts as a unifying upstream mechanism linking multiple PCD pathways during kidney injury. In acute kidney injury (AKI), ferroptosis and pyroptosis contribute prominently to early tubular injury, whereas persistent apoptosis, recurrent ferroptotic stress, and emerging copper-dependent metabolic vulnerability contribute to chronic kidney disease (CKD), diabetic kidney disease, glomerular injury, inflammation, and fibrosis. These pathways are interconnected through common stress signals, including reactive oxygen species accumulation, mitochondrial dysfunction, endoplasmic reticulum stress, Nrf2/Keap1-dependent antioxidant responses, inflammasome activation, and metal dysregulation. Understanding their temporal and compartment-specific activation is essential for distinguishing adaptive responses from irreversible damage. Targeting lipid peroxidation, inflammasome signaling, mitochondrial stability, apoptosis regulation, and copper metabolism may provide complementary strategies for limiting renal injury and preventing AKI-to-CKD transition. Future studies integrating multiomics approaches and disease-stage-resolved models will be required to define actionable cell-death signatures and enable precision interventions in kidney disease.