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

Sep 22, 2026

Metabolic reprogramming, especially enhanced lipid synthesis, is a key cancer feature that supports hepatocellular carcinoma (HCC) growth, yet the transcriptional regulators orchestrating lipid synthesis in HCC remain insufficiently defined. A genome-wide CRISPR/Cas9 knockout screen identifies ZNF217 as a central regulator. ZNF217 promotes de novo lipogenesis through binding and activating promoters of lipogenic enzymes, particularly FASN, driving proliferation, migration, invasion, tumor growth, and lung metastasis, with clinical relevance in patient samples.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages16

Reading Time40 min

AccessFree to download

Abstract

Background

Methods

Results

Conclusions

Introduction

Metabolic reprogramming and lipid metabolism

De novo synthesis and regulation

Study aims and rationale

Materials and methods

Cell lines and cell culture

Journal of Cancer Research and Clinical Oncology (2026) 152:164 [https://doi.org/10.1007/s00432-026-06535-4](https://doi.org/10.1007/s00432-026-06535-4) RESEARCH The transcription factor ZNF217 drives hepatocellular carcinoma progression by activating de novo lipid synthesis via FASN upregulation Yihui Fang1,2 · Ting Zhang1 · Tianxing Ye3 · Qizhen He4 · Qinong Ye1 Received: 8 January 2026 / Accepted: 3 June 2026 © The Author(s) 2026 Abstract Background 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. Methods 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. Results 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. Conclusions Our findings establish ZNF217 as a novel transcriptional regulator of lipid metabolism in HCC, linking its oncogenic function to the activation ofthe lipogenic pathway, and propose the ZNF217-FASN axis as a candidate therapeutic target for HCC treatment. Keywords De novo lipogenesis · Transcription factor · FASN · ZNF217 · Tumor growth · Tumor metastasis Yihui Fang, Ting Zhang and Tianxing Ye have contributed equally to this work and considered as co-first authors. 􀀍 Qinong Ye[yeqn88@163.com](yeqn88@163.com) 1 National Key Laboratory of Advanced Biotechnology, Academy of Military Medical Sciences, Beijing, China 2 Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang, China 3 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Beijing, China 4 First Clinical College, Liaoning University of Traditional Chinese Medicine, Shenyang, China Introduction Metabolic reprogramming is a defining hallmark of cancer, enabling malignant cells to sustain proliferation and survival in nutrient-fluctuating and often scarce microenvironments (Jiang et al. 2023; Lin et al. 2024a, 2024b; Perez et al. 2024) . Lipid metabolism, particularly the enhancement of lipid synthesis, plays a critical role in this process (Röhrig and Schulze 2016; Cheng et al. 2018; Li et al. 2021, 2024) . It provides not only essential membrane components and energy sources for tumor cells but also serves as signaling molecules that drive tumor progression. To meet heightened metabolic demands, cancer cells acquire lipids primarily through two pathways: de novo synthesis, involving the endogenous generation of fatty acids from acetyl-CoA, and exogenous uptake, where extracellular lipids are internalized via specific transportersand receptors (Butler et al. 2020) . De no

FAQs

What role does ZNF217 play in hepatocellular carcinoma progression?

ZNF217 functions as a transcription factor that activates de novo lipogenesis, thereby promoting HCC cell proliferation, migration, invasion, and in vivo tumor growth and lung metastasis.

How was ZNF217 identified as a regulator of lipid metabolism?

A genome-wide CRISPR/Cas9 knockout screen identified ZNF217. The regulatory effects were then supported by RNA sequencing, RT-qPCR, western blotting, and dual luciferase reporter assays.

Why is FASN important for ZNF217’s effects?

ZNF217-driven lipid synthesis and the downstream increases in proliferation, migration, and invasion depend on FASN expression, shown by pharmacological inhibition and genetic knockdown, and reflected in FASN-dependent tumor growth and metastasis in vivo.

Sep 22, 2026

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