<p>Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the development of multiple fluid-filled cysts in the kidneys, resulting in progressive decline and failure of renal function. Microsomal prostaglandin E synthase-2 (mPGES-2) is a unique bifunctional enzyme that catalyzes the conversion of prostaglandin H₂ (PGH₂) to prostaglandin E₂ (PGE₂) or to malondialdehyde (MDA) in conjunction with heme. PGE₂ and MDA are key mediators that regulate cell growth and proliferation, respectively. In this study, we elucidated the functional role of mPGES-2 in ADPKD. By performing Western blot and immunohistochemical staining on the kidneys of patients with PKD and healthy controls, we showed that the expression levels of mPGES-2 markedly increased. We then crossed mPGES-2 knockout (<i>Ptges</i>2^–/–) mice with <i>Ksp-</i>Cre; <i>pkd1</i>^flox/+ mice to generate mPGES-2 knockout ADPKD (<i>Ptges</i>2^–/–; PKD) mice. We showed that mPGES-2 depletion mitigated ADPKD progression in a mouse model. These findings were corroborated by in vitro experiments in embryonic kidney cells: the application of the mPGES-2 inhibitor SZ0232 (40, 80, and 160 μM) effectively suppressed cyst growth, suggesting a potential therapeutic option for ADPKD. Analysis of mPGES-2 metabolites revealed that mPGES-2 deficiency led to a reduction in PGE₂ production, which has not been detected in other renal diseases, likely because of the diminished heme levels in ADPKD kidneys. Moreover, mPGES-2 was implicated in the regulation of the downstream signaling pathway involving β-catenin/STAT3-c-Myc via PGE₂–EP₄, which promoted abnormal proliferation of renal tubular epithelial cells and influenced cyst formation. Our findings suggest that targeting mPGES-2 is a viable therapeutic strategy for the management of ADPKD.</p>