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Very little is known about the mechanisms by which malignant ascites modulates the cancer-promoting activity of human peritoneal mesothelial cells (HPMCs). Because malignant ascites induces pro-tumoral senescence in HPMCs, here we examined if this effect could be driven by oxidative stress. The study showed that malignant ascites generated by serous ovarian tumors induced oxidative damage to the DNA (γH2A.X, 53BP1, 8-hydroxy-2'-deoxyguanosine) and lipids (8-isoprostane) in HPMCs as well as increased the production of mitochondrial superoxides and cellular peroxides in these cells. This activity coincided with increased activity of two enzymes involved in the mitochondrial production of oxidants, i.e. cytochrome c oxidase and NADH dehydrogenase, decreased mitochondrial inner membrane potential, increased mitochondrial mass, and increased the activity of peroxisome proliferator-activated receptor gamma coactivator-1 alpha. Increased production of superoxides and peroxides in cells subjected to the malignant ascites was effectively reduced when the fluid was pre-incubated with neutralizing antibodies against hepatocyte growth factor. Moreover, when HPMCs subjected to the malignant ascites were protected against oxidative stress with a spin-trap scavenger of reactive oxygen species, they displayed decreased expression of senescence-associated β-galactosidase and their potential to stimulate cancer cell adhesion, proliferation, and migration was significantly diminished. Collectively, our findings indicate that improved ovarian cancer cell progression in response to HPMCs exposed to malignant ascites may be associated with the development of profound oxidative stress in these cells., (Copyright © 2018 Elsevier Ltd. All rights reserved.)