Study explains how colorectal cancer cells maintain high iron levels

Researchers from the University of Michigan Health Rogel Cancer Center have discovered a key metabolic pathway that allows colorectal cancer cells to accumulate large quantities of iron.

Blocking that pathway reduced iron levels and caused the cancer cells to die.

Scientists know that colorectal cancer cells require large amounts of iron and that as cancer becomes more aggressive, the cells have even higher amounts of iron.

Normal cells with high levels of iron would undergo a type of iron-related cell death called ferroptosis.

But in cancer cells, the iron continues to accumulate well beyond normal levels without succumbing to expected cell death processes.

In this new study, published in Cell Metabolism, researchers started by looking at the known pathways involved in ferroptosis, assuming something in this process was awry.

But knocking out these typical ferroptotic enzymes had no impact on tumor growth. So they dug deeper into mitochondrial metabolism.

Researchers conducted a metabolism-focused CRISPR screen, which revealed that cellular heme, an iron-containing molecule, was protecting tumor cells against iron toxicity.

By investigating heme, they discovered a specific mitochondrial complex, complex II, was buffering iron-induced cell death by regulating coenzyme Q.

SEE ALSO: Hungry for more: Metabolism pathways make tumors sensitive or resistant to treatments.

“Complex II in colon cancer was absolutely critical for buffering iron toxicity. When we knocked complex II out in cell lines or mouse models, the requirement for iron turns very toxic because they have no way to buffer it, and so those cancer cells start to die,” said senior study author Yatrik Shah, Ph.D., Horace W. Davenport Collegiate Professor of Physiology at Michigan Medicine.

Cancer cells carry extremely large amounts of iron compared to normal cells, so researchers suspect that knocking out this iron buffer will not affect normal cells.

They observed few side effects when knocking out complex II in mouse models.

This could make complex II a promising target against colorectal cancer.

In addition to complex II buffering iron toxicity, researchers also saw that iron itself was regulating complex II.

This is a potential additional area of study that could imply multiple ways to break the cycle.

There is already research focused on inhibiting mitochondrial reactions like this.

The next steps for the Rogel team will be assessing whether an inhibitor can apply to colorectal cancer.

Also, since many cancer types are similarly addicted to iron, further studies will look at whether the same or similar mechanisms are occurring in other cancers.

Additional authors: Chesta Jain, Muqit Essani, Roshan Kumar, Nupur K. Das, Rashi Singhal, Nicholas J. Rossiter, Brandon Chen, Wesley Huang, Zheng Hong Lee, Sumeet Solanki, Yuezhong Zhang, Peter Sajjakulnukit, Li Zhang, Prathana J. Dalal, David A. Hanna, Cristina Castillo Apaza, Harrison S.Greenbaum, Shannon E. McCollum, Elena M. Stoffel, Joel K. Greenson, L. James Maher III, Costas A. Lyssiotis, Ruma Banerjee

Funding: National Institutes of Health grants R01 CA148828, R35 GM130183, R37 CA237421, R01 CA248160, R01 CA244931, P30 CA046592, T32 GM150581, F99 CA284256-01, T32 CA009357, 1F31 DK143736-01; Rackham Babour Fellowship; Crohn’s and Colitis Foundation Research fellow award (623914); University of Michigan Pioneers Fellowship; the Paradifference Foundation

Paper cited: “Iron addicted colorectal cancers exploit heme-complex II axis to resist oxidative cell death,” Cell Metabolism. DOI: 10.1016/j.cmet.2026.04.020

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