OPLAH (5-oxoprolinase, ATP-hydrolysing) catalyzes the ATP-dependent cleavage of 5-oxo-L-proline to generate L-glutamate, functioning as a critical regulator within the glutathione metabolic cycle 1. Operating as a cytosolic enzyme, OPLAH prevents the accumulation of its substrate 5-oxoproline, which accumulates during glutathione catabolism and serves as a signaling molecule 2. OPLAH dysregulation associates with multiple disease states. OPLAH downregulation in heart failure leads to 5-oxoproline accumulation, oxidative stress, and worse clinical outcomes, while OPLAH overexpression improves cardiac function after ischemic injury 2. In a complementary role, exogenous 5-oxoproline supplementation protects against doxorubicin-induced cardiotoxicity while modulating OPLAH activity for therapeutic benefit 3. In skeletal muscle of type 2 diabetes models, OPLAH downregulation increases reactive oxygen species, reduces glutathione content, and impairs glucose uptake through PI3K/Akt/GLUT4 pathway inhibition 4. Additionally, OPLAH expression stratifies prognosis in esophageal squamous cell carcinoma, with elevated OPLAH independently predicting poor survival 5. Genetic variants in OPLAH associate with 4.8-fold increased risk of L-asparaginase-induced hypersensitivity in pediatric leukemia patients 6, while OPLAH expression regulation through RNA splicing impacts triple-negative breast cancer response 7.