NSUN5 is an S-adenosyl-L-methionine-dependent methyltransferase that catalyzes 5-methylcytosine (m5C) modification at cytosine 3782 in 28S rRNA 1, promoting protein translation without affecting ribosome biogenesis 2. Beyond its canonical rRNA methylation function, NSUN5 exhibits broader RNA methyltransferase activity, modifying chr7-associated RNAs and mRNAs of various genes including ACC1, GPX4, CTNNB1, SMAD3, and ZBED3 34567. Mechanistically, NSUN5-mediated m5C modifications enhance mRNA stability and translation of oncogenic targets, facilitating tumor progression across multiple cancer types 647. In hepatocellular carcinoma and prostate cancer, elevated NSUN5 promotes epithelial-mesenchymal transition and lipid accumulation through SMAD3 and ACC1 pathways, respectively 64. In glioma, NSUN5 recruits TET2 to convert m5C to 5-hydroxymethylcytosine on mRNAs like CTNNB1, promoting immune evasion through enhanced CD47 expression 3. Clinically, NSUN5 dysregulation associates with poor prognosis in HCC and glioblastoma 78, and altered NSUN5 expression participates in sepsis pathogenesis 9. Additionally, NSUN5 deficiency impairs somatosensory cortex development and pain perception 10, supporting roles in neurological function.