HBS1L (HBS1 like translational GTPase) is a GTPase component of the Pelota-HBS1L complex that serves as a critical ribosomal rescue factor in mRNA quality control 1. The complex recognizes ribosomes stalled at the 3' end of mRNAs and triggers the No-Go Decay (NGD) pathway by destabilizing mRNA in the ribosomal decoding center 1. Following mRNA extraction by the SKI complex, Pelota-HBS1L recruits ABCE1 to drive stalled ribosome disassembly and subsequent degradation of damaged mRNAs 2. HBS1L functions as SKI7, coupling the cytoplasmic exosome to ribosome-bound SKI2 helicase, forming an exosome-ribosome supercomplex that enables coordinated mRNA decay during translation 2. Clinically, HBS1L variants have significant disease relevance. Mutations causing HBS1L deficiency result in congenital anomalies, severe growth restriction, developmental delay, and retinal pigmentary deposits, associated with Pelota depletion and abnormal 80S monosome accumulation 3. In sickle cell disease, HBS1L-MYB genetic variants are major modifiers of fetal hemoglobin levels and disease severity 456. Additionally, the PELO-HBS1L complex represents a novel synthetic lethal therapeutic target in cancers with SKI complex destabilization, including 9p21.3-deleted and microsatellite-instability-high tumors 7.