NOX4 Suppresses Ferroptosis Through Regulation of the Pentose Phosphate Pathway in Colorectal Cancer

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Pathways

Background:

• Nicotinamide adenine dinucleotide phosphate (NADPH) oxidases (NOXs) generate reactive oxygen species (ROS), but their role in cellular antioxidant metabolism and ferroptosis remains unclear.
• Investigating NOX family members' expression and clinical significance in various cancers is crucial for understanding their broader impact.

Purpose of the Study:

• To assess the expression and clinical relevance of NOXs across pan-cancer.
• To investigate the specific role of NOX4 in colorectal cancer (CRC) progression and its potential as a therapeutic target.

Main Methods:

• Analysis of transcriptomic and survival data from The Cancer Genome Atlas (TCGA) for NOXs in 22 solid tumors.
• Utilized CRISPR screening in CRC cells to identify essential NOX targets.
• Employed CRISPR-knockout cell lines, 1,2-¹³C-glucose tracing, PI staining, BrdU assays, and coimmunoprecipitation to elucidate NOX4 function.

Main Results:

• NOX4 was identified as a key therapeutic target in colorectal cancer through TCGA data analysis and CRISPR screening.
• Upregulation of NOX4 was confirmed to promote CRC cell survival and proliferation.
• NOX4 interacts with glucose-6-phosphate dehydrogenase (G6PD) to enhance the pentose phosphate pathway (PPP), which aids in ROS clearance and protects CRCs from ferroptosis.

Conclusions:

• NOX4 acts as a novel suppressor of ferroptosis and presents a viable therapeutic target for colorectal cancer treatment.
• The study reveals a critical coupling between NOX4 and the PPP in regulating ferroptosis.
• This interaction uncovers a metabolic vulnerability in colorectal cancer that can be exploited for therapeutic interventions.