Zfp217 Regulates Hepatic de Novo Lipogenesis via METTL3-Mediated N6-Methyladenosine Modification of SREBF1

Zinc finger protein 217 (Zfp217) mediates adipogenesis via an N6-methyladenosine (m⁶A)-dependent mechanism; however, its role in hepatic lipid metabolism is unexplored. Nonalcoholic fatty liver disease (NAFLD), characterized by hepatic triglyceride (TG) accumulation resulting from disrupted lipid homeostasis, lacks well-defined epigenetic regulatory mechanisms. Here, we report that global Zfp217 heterozygous knockout alleviates high-fat diet (HFD)-induced hepatic steatosis in mice, as evidenced by reduced liver weight, decreased hepatic and serum TG and total cholesterol (T-CHO) levels, and hepatic lipid deposition. Mechanistically, Zfp217 deficiency suppresses hepatic de novo lipogenesis (DNL) by down-regulating sterol regulatory element-binding transcription factor 1 (SREBF1), a master regulator of lipogenic gene expression. Zfp217 physically interacts with methyltransferase-like 3 (METTL3) to repress its expression, thereby reducing m⁶A modification of SREBF1 mRNA at a specific coding sequence (CDS) site. Loss of Zfp217 enhances METTL3-dependent m⁶A modification at a specific site of SREBF1 mRNA, which promotes YTH domain-containing family protein 2 (YTHDF2)-mediated degradation of SREBF1 transcripts. Conversely, our findings identify a novel Zfp217-METTL3-m⁶A-YTHDF2-SREBF1 regulatory axis that controls hepatic DNL and NAFLD progression, establishing Zfp217 as a potential therapeutic target for NAFLD.