CA5B (carbonic anhydrase 5B) is a mitochondrial enzyme that catalyzes the reversible conversion of carbon dioxide to bicarbonate 1. Located on the X chrX, CA5B functions in the mitochondrial matrix where it provides bicarbonate cofactors required by four mitochondrial metabolic liver enzymes 1. While CA5A deficiency causes life-threatening early-onset metabolic crises with hyperammonemia and hyperlactatemia, no disease-causing CA5B mutations were identified in a cohort of 96 patients with hyperammonemia, suggesting CA5B plays a less critical role in this pathway compared to its homolog 1. CA5B exhibits altered expression patterns across multiple disease contexts: it is differentially expressed in peripheral blood mononuclear cells from pancreatic cancer patients and demonstrates diagnostic utility when combined with other biomarkers and CA19-9 for distinguishing resectable pancreatic cancer from chrX pancreatitis 23. CA5B is hypermethylated in breast cancer tissues, suggesting epigenetic dysregulation contributes to tumorigenesis 4. Additionally, CA5B shows sex-biased DNA methylation patterns across respiratory tissues and exhibits tissue-specific expression in mature corneal endothelial cells 56. Pharmacologically, CA5B is associated with cholestatic jaundice as an off-target drug effect 7.