PTGR2 (prostaglandin reductase 2) is an NADPH-dependent enzyme that catalyzes the reduction of 15-keto-PGE2 to 13,14-dihydro-15-keto-PGE2, representing a key step in prostaglandin metabolism and inflammatory regulation 1. The enzyme demonstrates highest activity toward 15-keto-PGE2, functioning through a mechanism involving conformational changes in LID motifs and critical tyrosine residues (Tyr64 and Tyr259) that are essential for catalysis 1. PTGR2's primary physiological role involves terminating prostaglandin signaling and modulating PPARγ activity, as 15-keto-PGE2 serves as an endogenous PPARγ ligand 2. Disease relevance is significant across multiple pathologies: PTGR2 acts as a putative oncogene overexpressed in pancreatic adenocarcinoma, where its inhibition induces oxidative stress-mediated cancer cell death 3. In metabolic disorders, PTGR2 inhibition represents a therapeutic strategy for diabetes and obesity by increasing endogenous PPARγ ligands without typical thiazolidinedione side effects 2. The enzyme also contributes to inflammatory responses in sepsis, where PTGR2 disruption improves survival by accumulating anti-inflammatory 15k-PGE2 and activating NRF2-mediated antioxidant pathways 4. Clinical significance extends to cancer therapy resistance, as PTGR2 represents a potential target for overcoming sunitinib resistance in renal cell carcinoma through interactions with KDM6A 5.