HPGD encodes 15-hydroxyprostaglandin dehydrogenase, an NAD-dependent enzyme that inactivates prostaglandins and related eicosanoids and docosanoids, including resolvins. It catalyzes oxidation of prostaglandin E2 (PGE2) and other hydroxylated polyunsaturated fatty acids to their keto metabolites, thereby suppressing pro-proliferative and pro-inflammatory signaling. By reducing PGE2 levels, HPGD acts as a tumor suppressor; downregulation of HPGD in multiple cancers allows PGE2 accumulation that promotes stemness, proliferation, and angiogenesis. In cholangiocarcinoma, bile exosomal miR-182/183-5p suppresses HPGD expression, increasing PGE2 and VEGF-A to drive cancer progression 1. Similarly, in liver cancer, ENO1-mediated suppression of HPGD activates PGE2-dependent tumorigenesis, which aspirin can inhibit 2. In cervical cancer, low HPGD correlates with reduced immunotherapy sensitivity and disease progression 3. Biallelic HPGD loss-of-function mutations cause primary hypertrophic osteoarthropathy (PHO), a hereditary disorder characterized by digital clubbing, periostosis, and pachydermia due to elevated systemic PGE2 4, 5. HPGD also regulates hypoxic pulmonary hypertension by controlling vascular remodeling 6. These findings position HPGD as a key suppressor of both cancer progression and prostaglandin-driven systemic pathology.