Regulatory roles and translational potential of the Kruppel-like factor family in liver disease

The Kruppel-like factor (KLF) family comprises transcription factors that share conserved zinc-finger domains and orchestrate key pathophysiological processes in the liver, including glucose and lipid metabolism, inflammatory responses, and fibrogenesis. In this review, we systematically dissect the roles of major KLF members—specifically KLF2–KLF10, KLF14, KLF15, and KLF16—in the pathogenesis of metabolic dysfunction-associated steatotic liver disease (MASLD), liver fibrosis/cirrhosis, and hepatocellular carcinoma (HCC). We discuss several key findings. First, KLF16 drives fatty acid β-oxidation by activating peroxisome proliferator-activated receptor alpha (PPARα), whereas KLF4 and KLF2 suppress de novo lipogenesis through the inhibition of SREBP-1c. Second, with respect to hepatic stellate cell activation, KLF6 and KLF5 promote fibrogenesis, whereas KLF14 has anti-fibrotic effects through the upregulation of peroxisome proliferator-activated receptor gamma (PPARγ). Third, in HCC, KLF2, KLF4, and KLF6 act as tumour suppressors, and are frequently epigenetically silenced, whereas KLF5, KLF7, and KLF8 function as oncogene products, by modulating Wnt/β-catenin signaling, glycolysis, and immune evasion. Last, emerging modalities, such as proteolysis-targeting chimeras and cell type-specific nanoparticle delivery, are described. These represent potential new avenues for KLF-targeting therapy. By delineating these context-dependent mechanisms, we provide a theoretical framework for the development of KLF-based precision strategies for the treatment of major liver diseases.