Bazedoxifene rescues hepatocytes from chemically induced oxidative ferroptotic injury in vivo and in vitro by inhibiting protein disulfide isomerase.

Acetaminophen-induced liver injury remains a major public health challenge and is characterized by glutathione depletion and oxidative stress, which are key features of oxidative ferroptosis. Protein disulfide isomerase (PDI) has been identified as an upstream mediator of chemically induced oxidative ferroptosis and also a target for therapeutic intervention. In this study, we demonstrated that bazedoxifene (BAZ), a selective estrogen receptor modulator, can strongly rescue chemically induced hepatocyte ferroptosis both in vitro and in vivo by inhibiting PDI's catalytic activity. Specifically, in the mouse model, BAZ effectively alleviates acetaminophen-induced liver injury, improves serum biochemical parameters, and reduces hepatic lipid peroxidation. In cultured hepatocytes, BAZ strongly suppresses chemically induced oxidative ferroptosis through inhibiting PDI-mediated nitric oxide synthase dimerization (i.e., catalytic activation), which prevents the accumulation of cellular nitric oxide and reactive oxygen species. These findings establish BAZ as a PDI inhibitor capable of mitigating chemically induced oxidative hepatocyte injury through a novel, non-estrogen receptor-dependent mechanism.