CA9 (carbonic anhydrase 9) is a membrane-bound enzyme that catalyzes the reversible interconversion of carbon dioxide, water, bicarbonate, and hydrogen ions, functioning as a zinc-dependent carbonate dehydratase 1. The protein contains a signal peptide, proteoglycan-related region, catalytic carbonic anhydrase domain, transmembrane anchor, and intracytoplasmic tail 1. CA9 plays a critical role in intracellular pH homeostasis by regulating intracellular pH (pHi) through its enzymatic activity 23. In hypoxic and acidic tumor microenvironments, CA9 is upregulated primarily through HIF-1α-mediated transcription, enabling cancer cells to survive in hostile conditions 45. CA9 expression correlates with enhanced glycolytic metabolism and aerobic lactate production (Warburg phenotype) 3, and functionally links to metabolic reprogramming via regulation of stearoyl-CoA desaturase 1 (SCD1) and ferroptosis inhibition 67. CA9 is highly expressed in multiple cancers including pancreatic, renal, lung, brain (glioblastoma), ovarian, and hepatobiliary tumors, where elevated expression correlates with poor survival, chemoresistance, and aggressive phenotypes 2845. CA9 inhibition induces pH-dependent cancer cell death (alkaliptosis) and reduces tumor growth in preclinical models 2, while CA9 targeting enhances response to standard chemotherapy 53.