Metabolic control of renal cell fate in kidney disease: nutrient rewiring, senescence and fibrosis.

The kidney is a metabolically demanding organ in which epithelial, endothelial, stromal and immune compartments operate within spatially specialized nutrient and oxygen microenvironments. Renal metabolic remodeling is not uniformly harmful: transient changes can preserve adenosine triphosphate production, redox balance and tissue repair, whereas persistent nutrient stress can lock cells into maladaptive states. We therefore define metabolic control of renal cell fate as a three-level framework linking context modifiers (cell type, nephron segment, injury stage, sex, age and comorbidity), shared metabolic control modules and downstream fate decisions. In tubular epithelial cells, sustained loss of fatty acid oxidation (FAO), impaired oxidative phosphorylation (OXPHOS) and persistent glycolytic switching promote senescence, inflammatory secretion and failed repair. In podocytes, branched-chain amino acid (BCAA) overload, impaired serine metabolism and mitochondrial injury promote apoptosis, cytoskeletal instability and proteinuria. In renal endothelial cells, disturbed nitric oxide-redox coupling and mitochondrial stress contribute to barrier dysfunction, endothelial-to-mesenchymal transition and capillary rarefaction. In stromal and immune compartments, glycolysis, lactate signaling and macrophage-fibroblast crosstalk sustain inflammatory and matrix-producing states. Metabolic-epigenetic pathways involving nicotinamide adenine dinucleotide (NAD+), nicotinamide N-methyltransferase (NNMT) and lactate-derived histone lactylation further convert transient stress into pathological memory. This framework integrates spatial niche, injury duration and cell identity to explain how nutrient rewiring directs repair or progression and identifies stage-specific, cell-selective therapeutic opportunities in kidney disease.