Ferroptosis is a form of oxidative cell death and has become a chemotherapeutic 
target for cancer treatment. BAY 11-7085 (BAY), which is a well-known IκBα 
inhibitor, suppressed viability in cancer cells via induction of ferroptotic 
death in an NF-κB-independent manner. Reactive oxygen species scavenging, relief 
of lipid peroxidation, replenishment of glutathione and thiol-containing agents, 
as well as iron chelation, rescued BAY-induced cell death. BAY upregulated a 
variety of Nrf2 target genes related to redox regulation, particularly heme 
oxygenase-1 (HO-1). Studies with specific inhibitors and shRNA interventions 
suggested that the hierarchy of induction is Nrf2-SLC7A11-HO-1. SLC7A11 
inhibition by erastin, sulfasalazine, or shRNA interference sensitizes 
BAY-induced cell death. Overexperession of SLC7A11 attenuated BAY-inhibited cell 
viability. The ferroptotic process induced by hHO-1 overexpression further 
indicated that HO-1 is a key mediator of BAY-induced ferroptosis that operates 
through cellular redox regulation and iron accumulation. BAY causes 
compartmentalization of HO-1 into the nucleus and mitochondrion, and followed 
mitochondrial dysfunctions, leading to lysosome targeting for mitophagy. In this 
study, we first discovered that BAY induced ferroptosis via Nrf2-SLC7A11-HO-1 
pathway and HO-1 is a key mediator by responding to the cellular redox status.