TRIM21-mediated METTL3 degradation promotes PDAC ferroptosis and enhances the efficacy of Anti-PD-1 immunotherapy.

Pancreatic cancer remains the most lethal human malignancy with limited clinical benefits from currently available anticancer treatments. Ferroptosis has recently attracted great attention as a potential antineoplastic strategy. However, the study of ferroptosis in PDAC remains insufficient. This study revealed that Methyltransferase like 3 (METTL3), as a key oncogenic factor, is frequently upregulated and inhibits ferroptosis by stabilizing SLC7A11 mRNA in PDAC. In addition, we identified a novel post-translational modification of METTL3 and characterized specific regulatory mechanisms of METTL3 protein degradation. The E3 ligase TRIM21 mediated K48-linked polyubiquitination of METTL3 at the K459 site, leading to the proteasomal degradation of METTL3, which prevented tumor progression by promoting ferroptosis. Interestingly, the TRIM21-METTL3 axics mediated ferroptosis effectively increased the expression of immune checkpoint PD-L1 and strengthened antitumor immunity in pancreatic cancer. Together, our findings first elucidated the detailed molecular mechanism of METTL3 degradation and revealed the pivotal role of the TRIM21-METTL3 axis in regulating ferroptosis and antitumor immunity, which may serve as a potential target for pancreatic cancer treatment.