Ebselen protects XPC deficient cells from H2O2 induced oxidative stress through a potentially mitohormetic mechanism.

Xeroderma pigmentosum group C fibroblasts (XP-C) are characterized by chronic redox imbalance and elevated H2O2 levels, making them a good model for testing compounds with antioxidant potential for therapeutic purposes. Here, we investigated the effects of ebselen, a compound with glutathione peroxidase (GPx) mimetic activity, in the XP-C model. We found that ebselen behaves as a hormetic compound, protecting cells against H2O2-induced cytotoxicity at low doses but potentiating the cytotoxic effect at higher doses. Accordingly, when administered chronically, ebselen significantly reduces H2O2 production and p53 levels. However, acute treatment with ebselen causes a reduction in O2 consumption (OCR) and extracellular acidification rate (ECAR), indicative of decreased mitochondrial function and metabolic activity. In addition, acute ebselen treatment causes a reduction in the GSH/GSSG ratio and an increase in NRF-2 expression, suggesting that ebselen induces redox stress that triggers an adaptive response, characterizing a possible mitohormetic effect. The reduction in the GSH/GSSG ratio appears to be the initial trigger after acute treatment with ebselen, since concomitant treatment with NAC prevents the reduction in OCR, ECAR and NRF-2 activation, in addition to protecting XP-C cells against lethal doses of ebselen.