KLF15 as a Metabolic Gatekeeper Linking Drug Metabolism, Toxicity, and Precision Therapeutics

ABSTRACT Krüppel‐like factor 15 (KLF15) is emerging as a metabolic‐state‐sensitive regulator of hepatic endobiotic and xenobiotic metabolism. The strongest causal evidence comes from mouse liver, where KLF15 directly and indirectly controls phase I–III enzymes and transporters, thereby modulating the detoxification and disposition of acetaminophen, rifampicin, and cyclosporine A. Evidence from the heart, vasculature, skeletal muscle, kidney, and tumor models establishes broader roles in metabolic adaptation and stress responses, but direct effects on extrahepatic drug disposition remain largely untested. In this Perspective, we review the established KLF15‐drug metabolism relationship from mouse studies and inferential evidence from clinical data, as well as mechanistically plausible extrahepatic extensions. Furthermore, we discuss the translational potential of KLF15 as a biomarker or therapeutic target that may advance precision medicine.