Metabolic reprogramming and metabolic homeostasis in podocyte injury: novel mechanistic insights and natural product therapies

Podocyte injury and loss are major pathological features of proteinuria and renal dysfunction. Growing evidence has highlighted the contribution of metabolic reprogramming and disrupted metabolic homeostasis to podocyte injury in glomerular disease. Under pathological conditions, alterations in the local microenvironment, including hyperglycemia, lipid overload, mechanical stress, and inflammatory stimuli, can trigger maladaptive metabolic responses in podocytes, characterized by disturbances in glucose, lipid, and amino acid metabolism. These metabolic alterations may be accompanied by disrupted ion homeostasis and crosstalk with innate immune signaling, collectively aggravating the structural and functional damage of podocytes. However, pharmacological options that specifically target metabolic abnormalities in podocytes are limited. Natural products, including traditional Chinese medicine prescriptions, have shown potential for mitigating podocyte injury because of their capacity to act on multiple targets and pathways. A range of natural products may preserve podocyte integrity by correcting mitochondrial dysfunction, reducing oxidative stress, modulating metabolic substrate utilization, restoring ion homeostasis, and attenuating inflammatory responses. This review examines metabolic reprogramming and homeostatic disturbances in podocytes, outlines the mechanisms underlying podocyte metabolic dysfunction, and summarizes how natural products mitigate podocyte injury in glomerular diseases, such as diabetic kidney disease and membranous nephropathy, thereby offering perspectives on metabolic mechanisms and potential therapeutic targets for podocyte-directed interventions.