KLF15 is a zinc-finger transcription factor that functions as a critical metabolic and stress-response regulator across multiple tissues. In the heart, KLF15 regulates cardiac metabolism through interaction with mitochondrial signaling pathways; loss of cardiac mitochondrial protein translation upregulates KLF15 to restore metabolic balance and prevent heart failure 1. KLF15 also negatively regulates cardiac remodeling by repressing CCN2 expression and inhibiting hypertrophy-associated transcription factors MEF2A and GATA4 [UniProt]. In skeletal muscle, KLF15 mediates immobility-induced atrophy through a Piezo1/KLF15/IL-6 signaling axis; mice with skeletal muscle-specific KLF15 deficiency are protected from immobilization-induced muscle loss 2. KLF15 acts as a candidate gene for obesity and type 2 diabetes, potentially through effects on branched-chain amino acid metabolism 3. In the kidney proximal tubule, KLF15 is essential for maintaining fatty acid oxidation and preventing acute kidney injury and fibrosis; KLF15 co-occupies promoters of FAO genes (CPT1A, ACAA2) with PPARα, and loss of KLF15 exacerbates injury through impaired metabolic gene expression 4. KLF15 expression is regulated by glucocorticoids in the brain as part of stress-response transcriptomic reprogramming 5. In endothelial cells, KLF15 negatively regulates angiogenesis by transactivating VASN, which activates Notch1 signaling 6. These findings position KLF15 as a metabolic sentinel integrating stress signals with tissue-specific adaptive responses.