Figure 10 .

A schematic depiction of the proposed role of PDI in mediating chemically induced ferroptosis

Our earlier study showed that PDI in untreated HT22 cells is mostly present in its S-nitrosylated form, and GSH depletion is associated with S-denitrosylation of PDI [22]. Under conditions of cellular GSH depletion ( i. e., with an increased GSSG/GSH ratio), the reduced form of PDI is facilely converted to its oxidized form by ERO1. Oxidized PDI is the active form for catalyzing the conversion of the nNOS monomer to its dimer form, which then leads to increased formation of NO, followed by accumulation of cellular ROS and lipid ROS and ultimately ferroptotic cell death.