ZCCHC4 is an N6-methyladenosine (m6A) rRNA methyltransferase that catalyzes methylation of adenine at position 4220 of 28S rRNA 12. This m6A modification of 28S rRNA is essential for efficient global translation 13. Structurally, ZCCHC4 contains a methyltransferase domain integrated with GRF-type and C2H2 zinc finger domains plus a CCHC domain, creating a unified RNA-binding surface with an autoinhibitory conformation that regulates substrate specificity 4. Beyond its canonical rRNA methyltransferase function, ZCCHC4 functions as an RNA-binding protein with oncogenic roles. ZCCHC4 is aberrantly overexpressed in multiple human cancers including hepatocellular carcinoma, pancreatic cancer, colon cancer, lung cancer, and esophageal cancer 56. Its overexpression is associated with poor prognosis and chemoresistance to DNA-damaging agents 5. Mechanistically, ZCCHC4 promotes chemoresistance by inhibiting DNA-damage-induced apoptosis through interactions with long noncoding RNAs, blocking apoptotic signaling pathways 57. In esophageal cancer, ZCCHC4 knockdown increases reactive oxygen species levels, triggering S-phase arrest and enhancing cisplatin sensitivity 6. These findings identify ZCCHC4 as a potential therapeutic target for improving chemotherapy efficacy.