ALYREF promotes malignant behaviors and inhibits ferroptosis in colon cancer cells by stabilizing PCSK9 mRNA

Colon cancer is a prevalent malignancy causing significant global morbidity and mortality. The RNA methyltransferase Aly/REF export factor (ALYREF), which binds 5-methylcytosine (m5C)-modified messenger RNA, represents a potential diagnostic and therapeutic target in cancer. However, its specific role and mechanism in colon cancer progression remain unexplored. ALYREF expression was significantly elevated in colon cancer tissues and cell lines compared to normal controls. Depletion of ALYREF suppressed colon cancer cell proliferation, migration, and invasion, while simultaneously promoting apoptosis and ferroptosis. Analysis revealed proprotein convertase subtilisin/kexin type 9 (PCSK9) is highly expressed in colon cancer and positively regulated by ALYREF. Mechanistically, ALYREF directly bound to and stabilized PCSK9 messenger RNA in a manner dependent on m5C modification. Crucially, the anti-tumor effects resulting from ALYREF knockdown were reversed by overexpressing PCSK9. Consistent with cellular findings, silencing ALYREF significantly inhibited tumor growth in vivo using xenograft models. This study demonstrates that ALYREF drives colon cancer malignancy by stabilizing PCSK9 messenger RNA via m5C methylation, thereby enhancing PCSK9 expression. These findings establish the ALYREF/PCSK9 axis as a critical mechanism in colon cancer progression, highlighting its potential as a novel therapeutic target for intervention.