Ying Zhu, Zuli Jiang, Youming Chen, Hongchun Liu, Xuanzhi Wang, Hongshen Lu, Yang Li, Xiangzhuan Zhao, Ruike Zhang, Lingxiu Meng, Keyu Jin, Zeduo Xu, Longfeng Zhang, Zheng Wu, Kanghui Wu, Hongyang Liu, Huihui G, Junhu Wan
Lung adenocarcinoma (LUAD), the most common subtype of non-small cell lung cancer, remains a significant therapeutic challenge due to its high mortality rates, driven by both inherent and acquired resistance to standard therapies. Emerging evidence highlights the role of epitranscriptomic regulation, particularly RNA modifications such as 5-methylcytosine (m5C), in the pathogenesis of cancer. This study identifies TRDMT1 (DNMT2), an m5C methyltransferase, as a tumor suppressor in LUAD. It was found that TRDMT1 expression is significantly lower in LUAD tissues, and this reduction is associated with poor prognosis in patients. Functional assays indicated that TRDMT1 inhibits the proliferation, migration, and invasion of LUAD cells in vitro. Mechanistically, transcriptomic profiling and subsequent investigation revealed that TRDMT1 enhances the stability of transferrin receptor (TFRC) mRNA in an m5C-dependent manner. This post-transcriptional regulation leads to TFRC upregulation, which subsequently disrupts intracellular iron homeostasis, culminating in increased susceptibility to ferroptosis-an iron-dependent form of regulated cell death. Rescue experiments confirmed that the tumor-suppressive and pro-ferroptotic effects of TRDMT1 are mediated through TFRC. This study unveils a novel TRDMT1-TFRC regulatory axis that suppresses LUAD progression through the modulation of ferroptosis, highlighting this pathway as a promising therapeutic target for future interventions.