Pharmacological and toxicological roles of Kruppel-like factors (KLFs) in the cardiovascular system: a review.

Kruppel-like factors (KLFs) are transcription factors (TFs) increasingly implicated in cardiovascular pharmacology and toxicology through molecular mechanisms regulating endothelial function, macrophage polarization, and lipid metabolism. For example, KLF2/4 maintains endothelial homeostasis by modulating endothelial nitric oxide synthase (eNOS) activity and oxidative stress, and KLF4 additionally regulates smooth muscle cell phenotypic switch. KLF6 governs macrophage polarization and pyroptosis, while KLF15 modulates cardiomyocyte lipid metabolism, with dysregulation linked to cardiomyopathy. Not surprisingly, drugs such as statins and phytochemicals, as well as toxicants like ox-LDL, nanomaterials, and radiation, alter KLF expression via non-coding RNA (such as microRNA) or TFs, influencing endothelial cell activation, vascular smooth muscle cell phenotypic switch, macrophage inflammation, and cardiomyocyte apoptosis. KLF-dependent pathways intersect with key toxicological processes, such as autophagy, ferroptosis, and lipid dysregulation, culminating in atherosclerosis and heart failure. Despite preclinical advances demonstrating KLFs as therapeutic targets, clinical translation remains limited, with no KLF-targeted agents in active trials. Future studies should delineate tissue-specific KLF interactions, resolve KLFs' conflicting roles, and explore CRISPR-based KLF-targeting modulation. Bridging molecular mechanisms, such as KLF's regulation of phenotypic transformation pathways in smooth muscle cells, to drug discovery could yield novel therapies for cardiovascular diseases. The present review underscores the need for mechanistic and translational research to harness KLFs in cardiovascular pharmacotherapy and toxicant risk assessment.