RPL22 is a structural component of the large ribosomal subunit essential for cytoplasmic protein synthesis 12. Beyond its canonical ribosomal role, RPL22 functions as a splicing regulator that responds to nucleolar stress. Under ribosomal stress conditions, RPL22 accumulates in the nucleolus and directly binds MDM4 pre-mRNA intron 6, promoting exon 6 skipping to reduce MDM4 levels and activate p53 34. RPL22 also regulates splicing of its paralog RPL22L1 and other targets 4. Mechanistically, RPL22 coordinates rRNA synthesis activity with mRNA splicing through direct interactions with 28S rRNA and mRNA splice junctions 4. Clinically, RPL22 mutations are frequent in microsatellite instability-high (MSI-H) tumors, particularly endometrial and colorectal cancers, occurring in ~52% of MSI-H endometrial cases 56. RPL22 acts as a tumor suppressor; loss-of-function mutations promote oncogenic MDM4 induction and cell proliferation while reducing p53 activity 6. In non-MSI contexts, RPL22 deficiency delays cellular senescence by preventing nucleolar accumulation and heterochromatin destabilization 7. RPL22 mutations confer sensitivity to RNA Polymerase I inhibitors, offering therapeutic opportunities 4. RPL22 is also identified as a driver gene in adrenocortical carcinoma 8 and generates actionable neoantigens from splicing aberrations 9.