KLF transcription factors in metabolic kidney disease: from podocyte protection to tubulointerstitial fibrosis.

Metabolic kidney disease comprises renal disorders driven or worsened by systemic metabolic abnormalities, including diabetic kidney disease, obesity-related kidney injury, hyperuricemia-associated nephropathy, and metabolic syndrome-associated chronic kidney disease. Despite different triggers, these disorders share podocyte injury, glomerular endothelial dysfunction, tubular lipotoxicity, mitochondrial impairment, oxidative stress, inflammation, and tubulointerstitial fibrosis, indicating a common program of metabolic stress-induced renal cell reprogramming. Krüppel-like factors (KLFs) are zinc-finger transcription factors that regulate cell differentiation, metabolic homeostasis, redox balance, inflammation, vascular integrity, epithelial function, and tissue remodeling. Emerging evidence suggests that KLF family members function as cell-specific and disease-stage-dependent regulators linking metabolic disturbance to kidney injury and repair. KLF15, KLF2, and KLF4 generally maintain podocyte integrity, endothelial quiescence, tubular metabolic adaptation, mitochondrial homeostasis, and anti-inflammatory responses, whereas KLF5, KLF6, and possibly KLF10 promote tubular activation, immune recruitment, transforming growth factor-β signaling, fibroblast activation, and extracellular matrix deposition during chronic injury. This review summarizes current evidence on KLFs in metabolic kidney disease, highlights process-specific mechanisms across renal compartments, and discusses therapeutic opportunities, delivery challenges, and the potential value of KLF-related signatures as biomarkers. By integrating protective and pathogenic KLF programs, it provides a framework for understanding transcriptional control in metabolically stressed kidneys and progressive renal decline.