HPGD (15-hydroxyprostaglandin dehydrogenase) is a NAD-dependent oxidoreductase that catalyzes the dehydrogenation of hydroxylated polyunsaturated fatty acids, including prostaglandins, lipoxins, and resolvins, converting them to inactive keto metabolites 12. Its primary physiological role involves degrading pro-proliferative prostaglandin E2 (PGE2) and inactivating anti-inflammatory resolvins during inflammation resolution 23. HPGD functions as a tumor suppressor by limiting PGE2 accumulation 45. Decreased HPGD expression in hepatocellular carcinoma, cholangiocarcinoma, and cervical cancer correlates with increased PGE2 levels and cancer progression 456. Loss of HPGD promotes tumor stemness, invasion, and epithelial-mesenchymal transition through PGE2-PTGER1 signaling 5. HPGD downregulation also associates with chemotherapy resistance and immunosuppression 67. Germline HPGD mutations cause primary hypertrophic osteoarthropathy (PHO), characterized by digital clubbing, periostosis, and elevated PGE2 due to impaired degradation 89. HPGD also regulates hypoxic pulmonary hypertension progression through endothelial cell proliferation and vascular remodeling 10. These findings identify HPGD as both a crucial metabolic regulator and therapeutic target across multiple diseases.