Nsun4, also known as NOP2/Sun RNA methyltransferase 4, is a crucial 5-methylcytosine (m5C) methyltransferase. The m5C modification it mediates is involved in multiple biological processes such as RNA transcription, structure, and stability regulation. NSUN4 is related to pathways like the PI3K-AKT pathway and has significance in various cellular functions and disease-related processes [1,2,3,5,6]. Conditional Nsun4 mouse knockouts have been used to study its role in mitochondrial ribosomal biogenesis [4].

In conditional Nsun4 mouse knockouts, mitochondrial translation is abolished, indicating NSUN4's essential role in mitochondrial ribosomal biogenesis. It methylates cytosine 911 in 12S rRNA of the small subunit of mitochondrial ribosomes, and the NSUN4/MTERF4 complex is required for the assembly of the small and large subunits to form a monosome [4]. In glioma, loss-of-function experiments showed that NSUN4 enhances m5C modification of mRNA, promoting the malignant progression of glioma by regulating ALYREF binding to CDC42 mRNA and thus its stability [1]. In lung cancer, NSUN4-mediated m5C modification of circERI3 increases its nuclear export and promotes lung cancer development by altering mitochondrial energy metabolism [2]. In non-small cell lung cancer (NSCLC), inhibition of NSUN4 diminishes cell growth, stemness, invasiveness, and migratory ability in vitro and impedes the growth of subcutaneous xenografts in vivo [6].

In conclusion, NSUN4 is essential for mitochondrial ribosomal biogenesis through its role in rRNA methylation and ribosome assembly. Its m5C-mediated regulation also significantly impacts the development of various cancers including glioma, lung cancer, and NSCLC. Studies using Nsun4 KO/CKO mouse models have provided valuable insights into its functions in these disease-related biological processes.