WTAP-Mediated Glutaminase Splicing Bias Suppresses Ferroptosis in Hepatocellular Carcinoma - PubMed
9 hours ago
- #Glutaminase Splicing
- #Ferroptosis
- #Hepatocellular Carcinoma
- Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis, characterized by hyperactivation of the EGFR signaling pathway.
- Glutaminase (GLS) is commonly overexpressed in malignant tumors, acting as an oncogene to support cell growth and tumor progression.
- The study aimed to understand how EGFR activation drives glutaminolysis reprogramming and confers ferroptosis resistance in HCC.
- AKT, activated by EGFR signaling, phosphorylates WTAP S176, increasing its binding to METTL3, which promotes m6A modification of GLS pre-mRNA.
- This modification favors the alternative splicing of GLS towards GAC over KGA, leading to increased glutamine utilization and glutathione/NADPH biosynthesis.
- The switch to GAC alleviates ferroptosis and promotes tumor growth in mice.
- WTAP pS176 and GAC expression levels are mutually correlated and associated with poor prognosis in HCC patients.
- The findings highlight the therapeutic potential of targeting the m6A-dependent GLS isoform switch in HCC.