The transcription factor ZNF217 drives hepatocellular carcinoma progression by activating de novo lipid synthesis via FASN upregulation

Metabolic reprogramming, particularly enhanced lipid synthesis, is a hallmark of cancer that supports tumor growth and progression. However, the transcriptional regulators controlling this process in hepatocellular carcinoma (HCC) remain incompletely understood. A genome-wide CRISPR/Cas9 knockout screen identified ZNF217 as a key regulator of lipid metabolism in HCC. The regulatory effects of ZNF217 were analyzed using RNA sequencing, RT-qPCR, western blotting, and dual luciferase reporter assay. Intracellular lipid content was assessed using flow cytometry, oil red O staining, and triglyceride/cholesterol detection kits. Cell proliferation, migration, and invasion were assessed in vitro. In vivo tumor growth and metastasis were evaluated using nude mouse models. Clinical relevance was analyzed using immunohistochemical (IHC) staining, Kaplan–Meier survival analysis. We identify the transcription factor ZNF217 as a key activator of de novo lipogenesis in HCC. ZNF217 binds to and transactivates the promoters of critical lipogenic enzymes, including fatty acid synthase (FASN) and acetyl-CoA carboxylase 1 (ACC1). ZNF217-driven lipid synthesis, cell proliferation, migration, and invasion were dependent on FASN expression, as demonstrated by pharmacological inhibition and genetic knockdown. ZNF217 overexpression promoted HCC tumor growth and lung metastasis in a FASN-dependent manner in vivo. Clinically, ZNF217 was significantly upregulated in HCC tissues, positively correlated with FASN expression, and associated with poor patient survival. Our findings establish ZNF217 as a novel transcriptional regulator of lipid metabolism in HCC, linking its oncogenic function to the activation of the lipogenic pathway, and propose the ZNF217-FASN axis as a candidate therapeutic target for HCC treatment.