CLYBL (citramalyl-CoA lyase) is a mitochondrial enzyme that serves as a metabolic detoxification system, primarily protecting against vitamin B12-poisoning metabolites 12. The enzyme functions as a citramalyl-CoA lyase, converting citramalyl-CoA into acetyl-CoA and pyruvate in the C5-dicarboxylate catabolism pathway, which is essential for detoxifying itaconate, an antimicrobial metabolite that can inhibit B12-dependent enzymes 1. Additionally, CLYBL acts as a malyl-CoA thioesterase, removing malyl-CoA, a toxic side product of citric acid cycle enzymes that potently inhibits the B12-dependent methylmalonyl-CoA mutase 2. The enzyme also exhibits malate synthase activity, converting glyoxylate and acetyl-CoA to malate, and β-methylmalate synthase activity in vitro 3. CLYBL's clinical significance is evidenced by natural knockout variants in ~5% of humans, which are associated with reduced circulating vitamin B12 levels 31. Beyond metabolic functions, CLYBL plays regulatory roles in immune responses through acetylation-dependent mechanisms in macrophages 4 and tumor suppression in breast cancer 5. The gene serves as a genomic safe harbor for transgene integration in stem cell research 6.