Heme oxygenase-1 mediates BAY 11-7085 induced ferroptosis

Area of Science:

• Cellular Biology
• Oncology
• Biochemistry

Background:

• Ferroptosis, a form of oxidative cell death, is a promising chemotherapeutic target in cancer treatment.
• BAY 11-7085 (BAY), an IκBα inhibitor, demonstrates anti-cancer effects by inducing ferroptosis independently of NF-κB signaling.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying BAY-induced ferroptosis.
• To identify key mediators and pathways involved in BAY's anti-cancer activity.

Main Methods:

• Investigated the role of reactive oxygen species, lipid peroxidation, glutathione, and iron in BAY-induced cell death.
• Utilized inhibitors and shRNA to study the Nrf2-SLC7A11-HO-1 pathway.
• Examined the effects of Nrf2 target gene upregulation, particularly heme oxygenase-1 (HO-1).
• Assessed the impact of SLC7A11 inhibition and overexpression on BAY's efficacy.
• Studied HO-1 compartmentalization, mitochondrial function, and mitophagy.

Main Results:

• BAY-induced ferroptosis was rescued by interventions targeting oxidative stress, lipid peroxidation, glutathione, and iron.
• BAY upregulated Nrf2 target genes, notably HO-1, establishing an Nrf2-SLC7A11-HO-1 hierarchy.
• Inhibition of SLC7A11 sensitized cells to BAY, while its overexpression attenuated cell death.
• HO-1 overexpression induced ferroptosis, confirming HO-1 as a key mediator via redox regulation and iron accumulation.
• BAY induced HO-1 nuclear/mitochondrial compartmentalization, leading to mitochondrial dysfunction and mitophagy.

Conclusions:

• BAY 11-7085 induces ferroptosis through the Nrf2-SLC7A11-HO-1 pathway, with HO-1 acting as a critical mediator.
• HO-1's role in cellular redox regulation and iron accumulation is central to BAY-induced ferroptosis.
• The findings provide novel insights into ferroptosis induction and potential therapeutic strategies in cancer.