Programmed cell death in acute kidney injury: From molecular mechanisms to targeted therapies

Acute kidney injury (AKI) represents a formidable global health challenge characterized by high morbidity and mortality, yet effective pharmacological interventions remain elusive. Programmed cell death (PCD) pathways, orchestrating the depletion of renal tubular epithelial cells, are increasingly recognized as central drivers of AKI pathogenesis. Despite the rapid expansion of PCD-targeted agents in Other therapeutic areas, their translational potential in AKI has not been fully exploited. This review provides a systematic synthesis of the molecular mechanisms governing diverse PCD modalities in renal injury, including Apoptosis, Pyroptosis, Necroptosis, Ferroptosis, Cuproptosis, cellular senescence, and PANoptosis. We comprehensively analyze the intricate regulatory networks of these pathways and highlight emerging therapeutic targets, including transmembrane protein 16A (TMEM16A), signal transducer and activator of transcription 3 (STAT3), Glutathione Peroxidase 4 (GPX4), and Others. Furthermore, we evaluate the developmental status of promising investigational agents, ranging from small-molecule inhibitors and agonists to novel PROteolysis-TArgeting Chimera (PROTAC) degraders (e.g., targeting STAT3). By integrating recent mechanistic advances with preclinical pharmacological evidence, this review outlines a rational framework for developing precision therapeutics targeting PCD signaling nodes, paving the way for novel strategies to halt AKI progression and facilitate renal recovery.