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 (m 6 A)‐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 m 6 A modification of SREBF1 mRNA at a specific coding sequence (CDS) site. Loss of Zfp217 enhances METTL3‐dependent m 6 A 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‐m 6 A‐YTHDF2‐SREBF1 regulatory axis that controls hepatic DNL and NAFLD progression, establishing Zfp217 as a potential therapeutic target for NAFLD.