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.

Hepatocellular carcinoma (HCC) is characterized by its highly invasive and metastatic potential, as well as a propensity for recurrence, contributing to treatment failure and increased mortality. Under physiological conditions, the liver maintains a balance in lipid biosynthesis, degradation, storage, and transport. HCC exhibits dysregulated lipid metabolism, driving tumor progression and therapeutic resistance. This review aims to elucidate the roles of fatty acid, sphingolipid, and cholesterol metabolism in HCC pathogenesis and explore emerging therapeutic strategies targeting these pathways. Key findings demonstrate that upregulated enzymes like fatty acid synthase (FASN), acetyl-CoA carboxylase (ACC), enhance de novo lipogenesis and β-oxidation, and promote HCC proliferation, invasion, and apoptosis evasion. Sphingolipids exert dual functions: ceramides suppress tumors, while sphingosine-1-phosphate (S1P) drives oncogenic signaling. Aberrant cholesterol metabolism, mediated by HMG-CoA reductase (HMGCR), liver X receptor α (LXRα), and sterol regulatory element-binding protein 1 (SREBP1), contributes to immunosuppression and drug resistance. Notably, inducing ferroptosis by disrupting lipid homeostasis represents a promising approach. Pharmacological inhibition of key nodes—such as FASN (Orlistat, TVB-3664), sphingomyelin synthase (D609), or cholesterol synthesis (statins, Genkwadaphnin)—synergizes with sorafenib/lenvatinib and overcomes resistance. We conclude that targeting lipid metabolic reprogramming, alone or combined with conventional therapies, offers significant potential for novel HCC treatment strategies. Future efforts should focus on overcoming metabolic plasticity and optimizing combinatorial regimens.