Exogenous carbon monoxide promotes GPX4-dependent ferroptosis through ROS/GSK3β axis in non-small cell lung cancer

Area of Science:

• Biomedical research
• Cancer therapy
• Gas signaling molecules

Background:

• Gas therapy, particularly using carbon monoxide (CO), is gaining traction for treating various diseases, including cancer.
• CO is recognized for its anti-cancer properties, inducing cell death through autophagy, apoptosis, and necrosis.
• Ferroptosis, a recently identified programmed cell death pathway, is characterized by inflammation and lipid peroxidation.

Purpose of the Study:

• To investigate the potential of carbon monoxide (CO) in inducing ferroptosis as an anti-cancer strategy.
• To explore the underlying molecular mechanisms by which CO triggers ferroptosis.
• To evaluate the efficacy of CO delivered via CORM-3 in inducing ferroptosis both in vitro and in vivo.

Main Methods:

• Utilized a CO-releasing molecule 3 (CORM-3) to deliver low concentrations of CO.
• Investigated the induction of ferroptosis in cancer cells and in vivo models.
• Analyzed the modulation of the ROS/GSK3β/GPX4 signaling pathway.
• Measured the accumulation of lipid hydroperoxides as an indicator of ferroptosis.

Main Results:

• Low concentration CO delivered by CORM-3 effectively induced ferroptosis in cancer cells and in vivo.
• CO was found to modulate the ROS/GSK3β/GPX4 signaling pathway, leading to ferroptosis.
• The mechanism involves the accumulation of lipid hydroperoxides, a hallmark of ferroptosis.

Conclusions:

• Carbon monoxide (CO) effectively induces ferroptosis, a novel form of programmed cell death, in cancer.
• The ROS/GSK3β/GPX4 pathway is a key mediator of CO-induced ferroptosis.
• CO, delivered via CORM-3, shows promise as a potential ferroptosis inducer for future cancer therapies.