Inhibition of PHF1 promotes ferroptosis via IRES‐dependent Snail translation regulation in pancreatic ductal adenocarcinoma

Abstract Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with a poor prognosis and increasing global incidence. Although the epigenetic regulator plant homeodomain finger protein 1 (PHF1) is known for its transcriptional silencing function in cancer, its role in PDAC progression and translational regulation remains largely unexplored. Here, we report that PHF1 is significantly upregulated in PDAC and promotes the proliferation, migration, and invasion of PDAC cells. Mechanistically, PHF1 physically interacts with the fibrillarin (FBL)/NOP56/NOP58 snoRNP complex, facilitating its assembly and enhancing the internal ribosome entry site (IRES)‐dependent translation of Snail. Depletion of PHF1 reduces Snail levels, leading to ferroptosis sensitization in KRAS‐mutated PDAC cells. Additionally, PHF1 knockdown markedly reduces overall tumor burden in Kras‐mutated mice. In conclusion, our findings identify PHF1 as an oncogene that promotes PDAC progression and demonstrate that its inhibition induces ferroptosis via suppression of IRES‐dependent Snail translation. Thus, our findings reveal a previously unrecognized translational regulatory role of PHF1 and suggest its targeting as a promising therapeutic strategy for PDAC.