Simple SummaryBackground: Previous studies reported mitochondrial and endoplasmic reticulum (ER) redox stress in Circulating mononucleated cells (PBMCs) of patients with Hodgkin lymphoma (HL) display an oxidative damage to the endoplasmic reticulum. Here, we assessed whether the redox stress also characterizes tissues not directly involved in the inflammatory response and extends to non-HL (NHL) patients. Mitochondrial reactive oxygen species generation and malondialdehyde levels were increased only in the PBMCs of HL patients. These same cells also showed an enhanced activity of the hexose-6P-dehydrogenase (H6PD) and thus of a pentose phosphate pathway selectively confined within the ER. H6PD regulates the uptake of the most widely used tracer in clinical oncology:18F-fluoro-deoxyglucose whose uptake was remarkably increased in the heart of HL patients. These data thus document that HL is associated with a high redox stress involving the ER. This feature does not apply to NHL. It is not limited to the PBMCs, and rather involves the myocardium as an epitome of tissues not participating to the inflammatory response to the disease.AbstractBackground: Previous studies reported mitochondrial and endoplasmic reticulum redox stress in peripheral blood mononucleated cells (PBMCs) of treatment-naïve Hodgkin lymphoma (HL) patients. Here, we assessed whether this response also applies to non-HL (NHL) patients, and whether the oxidative damage is a selective feature of PBMCs or, rather, also affects tissues not directly involved in the inflammatory response. Methods: Isolated PBMCs of 28 HL, 9 diffuse large B cell lymphoma, 8 less aggressive-NHL, and 45 controls underwent flow cytometry to evaluate redox stress and uptake of the glucose analogue 2-NBDG. This analysis was complemented with the assay of malondialdehyde (MDA) levels and enzymatic activity of glucose-6P-dehydrogenase and hexose-6P-dehydrogenase (H6PD). In all lymphoma patients,18F-fluoro-deoxyglucose uptake was estimated in the myocardium and skeletal muscles. Results: Mitochondrial reactive oxygen species generation and MDA levels were increased only in HL patients as well as H6PD activity and 2-NBDG uptake. Similarly, myocardial FDG retention was higher in HL than in other groups as opposed to a similar tracer uptake in the skeletal muscle. Conclusions: Redox stress of PBMCs is more pronounced in HL with respect to both NHL groups. This phenomenon is coherent with an increased activity of H6PD that also extends to the myocardium.