RIOK3 is a serine/threonine-protein kinase with dual roles in ribosome quality control and innate immunity. Functionally, RIOK3 serves as a ubiquitin reader that recognizes ribosomal proteins uS3/RPS3 and uS5/RPS2 monoubiquitinated by the E3 ligase RNF10, promoting degradation of stalled 40S ribosomal subunits through progressive 18S rRNA decay 123. This quality control pathway activates downstream of the integrated stress response (ISR) mediated by GCN2 kinase, responding to conditions including amino acid starvation and ribosome subunit imbalance 13. Beyond ribosomal surveillance, RIOK3 regulates innate immune responses by phosphorylating IFIH1 to attenuate MDA-5 signaling and potentially recruiting TBK1 to IRF3 for type I interferon production 45. Disease relevance includes roles in viral infections; RIOK3 expression increases during enterovirus infection and facilitates CVB3 replication through CDC42 suppression 6, while alternatively spliced RIOK3 isoforms exhibit opposite effects on antiviral responses during Rift Valley fever virus infection 7. Clinically, RIOK3 demonstrates utility as an immunological and prognostic biomarker across multiple cancers, correlating with immune infiltration and checkpoint marker expression 8, and promotes PDAC progression via arginine metabolism regulation 9.