SKIC3 (SKI3) is a critical component of the superkiller (SKI) complex, a multiprotein assembly that mediates mRNA quality control and decay pathways 1. The SKI complex catalyzes 3'-5' directional mRNA extraction from stalled 80S ribosomes and channels extracted transcripts to the cytosolic exosome for degradation 2. This function is essential for ribosome recycling, as SKI-mediated mRNA removal allows subsequent binding of the Pelota-HBS1L complex and ABCE1-dependent ribosome disassembly 1. In the nucleus, SKIC3 cooperates with the PAF1 complex at transcriptionally active genes, contributing to nuclear mRNA surveillance 2. SKIC3 dysfunction has significant clinical consequences. Biallelic mutations in SKIC3 cause trichohepatoenteric syndrome (THES-1), characterized by neonatal-onset intractable diarrhea, growth retardation, hair abnormalities, facial dysmorphism, and progressive liver disease requiring long-term total parenteral nutrition 34. Additionally, MSI-H cancers with deleterious TTC37/SKIC3 mutations exhibit synthetic lethality with PELO depletion, as SKI complex destabilization forces reliance on PELO for managing mRNA extracted from stalled ribosomes; PELO inhibition triggers the unfolded protein response in these cancer cells 1. These findings underscore SKIC3's essential roles in developmental homeostasis and cellular stress responses.