Oxidative stress induced by reactive oxygen intermediates has been implicated in a variety of human diseases including rheumatoid arthritis and neurodegenerative disorders. 15-Deoxy-Delta(12,14)-prostaglandin J(2) (15d-PGJ(2)), a terminal dehydration product of prostaglandin D(2), is an endogenous ligand of peroxisome proliferator-activated receptor-gamma and exhibits a number of biological activities including the proapoptotic activity. Recent studies have revealed that this cyclopentenone prostaglandin, at non-toxic concentrations, can also exert antiapoptotic or cytoprotective effects. In this study, the underlying mechanisms involved in the protective effects of 15d-PGJ(2) on the H2O2-induced cytotoxicty were explored using cultured rat pheochromocytoma (PC12) cells. PC12 cells treated with H2O2 underwent apoptosis, which was attenuated by pretreatment with non-toxic concentrations of 15d-PGJ(2). Treatment of the PC12 cells with 15d-PGJ(2) resulted in increased nuclear translocation, DNA-binding and transcriptional activity of NF-E2-related factor 2 (Nrf2), leading to upregulation of heme oxygenase-1 (HO-1) expression, which provided an adaptive survival response against the H2O2-derived oxidative cytotoxicity. Transfection of PC12 cells with dominant-negative Nrf2 gene abolished the 15d-PGJ(2)-derived induction of HO-1 expression. Moreover, the 15d-PGJ(2)-mediated increases in Nrf2-ARE binding and ARE luciferase activity were suppressed by the dominant-negative mutation as well as the pharmacological inhibition of Akt/protein kinase B or extracellular signal-regulated kinase 1/2 (ERK1/2). Taken together, these findings suggest that 15d-PGJ(2) augments cellular antioxidant defense capacity through activation of Akt and ERK signal pathways that leads to Nrf2 activation, and subsequently HO-1 induction, thereby protecting the PC12 cells from H2O2-induced oxidative cell death.