RPL3 is a structural component of the large ribosomal subunit (60S) essential for protein synthesis in eukaryotic cells 123. RPL3 undergoes histidine methylation at His-245 by the methyltransferase METTL18, a modification important for optimal ribosome biogenesis and function 4. RPL3 expression is tightly autoregulated through an alternative splicing-nonsense-mediated mRNA decay (AS-NMD) mechanism involving splicing factors hnRNP H1, NPM, and KHSRP, whereby RPL3 overexpression promotes production of decay-targeted mRNA isoforms 56. Tissue-specific RPL3 paralogue RPL3L modulates RPL3 expression levels and influences ribosomal subcellular localization and mitochondrial activity in cardiomyocytes, though not translational efficiency of specific transcripts 7. Clinically, RPL3 downregulation occurs in Phelan McDermid syndrome (PMS) associated with SHANK3 mutations, and restoring RPL3 expression rescues protein synthesis deficits and behavioral abnormalities in Shank3 knockout mice 8. Additionally, mutations in RPL3 confer resistance to linezolid antibiotic therapy and DON toxin, highlighting its role in drug and toxin sensitivity 910.