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.