Abstract

Kruppel‐like factors (KLFs) constitute a crucial family of transcription factors that are engaged in a variety of biological processes, such as erythropoiesis as well as liver development. A growing body of research underscores the increasing importance of the KLF family in the context of hepatocellular carcinoma (HCC). Despite this, the exact function of KLF1 within HCC remains unclear. Our study demonstrates a significant upregulation of KLF1 expression in tumour samples from HCC patients compared to normal liver tissue, with higher expression levels strongly correlating with poorer survival outcomes. Notably, in vitro experiments have shown that KLF1 enhances liver cancer cell proliferation by inhibiting ferroptosis, and this inhibition is negatively correlated with the transcription levels of fatty acid synthase 4 (ACSL4). These findings suggest that KLF1 may exert its oncogenic potential by repressing ferroptosis through the inhibition of ACSL4 transcription. Further mechanistic investigations reveal that KLF1 inhibits ACSL4 expression via transcriptional repression and suppresses ferroptosis through the ACSL4/LPCAT3 axis, ultimately promoting HCC tumour growth as well as its advancement. In conclusion, KLF1 is essential for onset as well as development in HCC through inhibiting ACSL4 transcription along with ferroptosis, thereby presenting novel therapeutic targets for HCC treatment.