Ythdc1, the YTH domain containing 1, is a nuclear N6-methyladenosine (m6A) reader protein. m6A modification is a key regulator of gene expression and Ythdc1 is involved in multiple RNA-related processes such as mRNA splicing, export, and stability regulation. It is associated with various biological pathways including those related to cell proliferation, autophagy, and ferroptosis, and is of great biological importance in normal development and disease [1,2,3,4]. Genetic models, like KO/CKO mouse models, are valuable for studying its functions.

In acute myeloid leukemia (AML), genetic deletion of Ythdc1 in mice markedly blocks AML development, maintenance, and self-renewal of leukemia stem cells (LSCs), indicating its oncogenic role in AML by regulating MCM4-mediated DNA replication [5]. In lung cancer, YTHDC1 knockdown promotes lung tumor progression and upregulates FSP1 protein level, leading to ferroptosis resistance. Mechanistically, YTHDC1 binding to the m6A sites in the FSP1 3'-UTR recruits CSTF3 to generate a less stable shorter 3'-UTR FSP1 mRNA [2]. In diabetic skin, knockdown of Ythdc1 in keratinocytes affects autophagic flux, apoptosis, and wound-healing capacity, as it drives SQSTM1 mRNA degradation in the nucleus [3].

In conclusion, Ythdc1 is crucial in regulating mRNA-related processes and is involved in various disease conditions. Gene knockout mouse models have revealed its role in cancer development, such as in AML and lung cancer, as well as in diabetic skin wound-healing impairment. Understanding Ythdc1's functions provides insights into disease mechanisms and potential therapeutic targets.