Podocyte Metabolic Reprogramming and Targeted Therapy

Abstract Podocytes, highly specialized glomerular epithelial cells, are essential for maintaining the filtration barrier integrity, yet they are particularly susceptible to metabolic stress. Recent advances have identified metabolic reprogramming as a central driver of podocyte injury in diverse glomerular diseases, including diabetic kidney disease and focal segmental glomerulosclerosis. Pathological stimuli, such as hyperglycemia, lipotoxicity, oxidative stress, and inflammatory cytokines, lead to profound alterations in podocyte metabolism, encompassing dysregulation of lipid, glucose, amino acid, and ion handling, as well as activation of immunometabolic pathways. These maladaptive changes result in mitochondrial dysfunction, cytoskeletal disorganization, and inflammatory forms of cell death including pyroptosis and ferroptosis. Mechanistic studies have elucidated the roles of nutrient-sensing pathways (AMPK, mTOR, SIRT1), innate immune sensors (NLRP3, cGAS–STING), and metabolic enzymes (CerS6, GLS2, ODC1) in orchestrating this reprogramming. Emerging evidence supports the therapeutic potential of modulating podocyte metabolism, as exemplified by the renoprotective effects of SGLT2 inhibitors, GLP-1 receptor agonists, PPAR agonists, and targeted inhibitors of inflammasome or lipid pathways. This Review synthesizes recent insights into the structural-metabolic coupling in podocytes, dissects the mechanisms of metabolic derangement in disease contexts, and discusses promising therapeutic strategies aimed at restoring metabolic homeostasis. Understanding the intersection between podocyte metabolism and injury response offers novel avenues for the prevention and treatment of chronic glomerular diseases.