WDR5‐H3K4me3 Epigenetic Axis Promotes TRMT6‐Dependent tRNA M ¹ A Modification to Facilitate Triple‐Negative Breast Cancer Progression by Suppressing Ferroptosis

Abstract N ¹ ‐methyladenosine (m ¹ A) modification widely occurs in various RNAs, yet its pathophysiological function in tumorigenesis remains poorly understood. Notably, the expression and biological roles of tRNA m ¹ A methyltransferase 6 noncatalytic subunit (TRMT6) in breast cancer, particularly in triple‐negative breast cancer (TNBC), are unknown. Herein, it is demonstrated that TRMT6 is markedly elevated in TNBC, due to the H3K4me3 methylation modification occurring at the promoter region to enhance transcription. Through integrated analyses of m ¹ A tRNA methylated RNA immunoprecipitation sequencing, ribosome profiling sequencing, RNA sequencing and data‐independent acquisition mass spectrometry, ferritin heavy chain 1 (FTH1) is identified as a downstream target of TRMT6. Mechanistically, it is found that TRMT6 is responsible for the formation of m ¹ A methylation on tRNAs, which increases the translation efficiency of FTH1. Besides, TRMT6 promotes ferritin light chain (FTL) expression at both transcriptional and translational levels, further reinforcing its role in iron metabolism. TRMT6 regulates the malignant progression of TNBC by modulating ferroptosis in tumor cells. Conclusively, the findings indicate that histone methylation‐driven TRMT6 is crucial for the translation of FTH1 and FTL, which bridges the understanding of m ¹ A tRNA modification and ferroptosis. These results highlight TRMT6 as a novel potential therapeutic target for TNBC.