Microbial regulation of ferroptosis in cancer Original paper

What was reviewed?

This News & Views piece reviewed how microbiome-derived metabolites can shape cancer behavior by changing ferroptosis sensitivity in tumor cells. It centered on a new mechanism linking a gut bacterial tryptophan metabolite, trans-3-indoleacrylic acid (IDA), to colorectal cancer progression through ferroptosis suppression. The authors emphasized that microbial metabolites can remodel tumor signaling and microenvironments, and they framed ferroptosis control as a clinically relevant lever because ferroptosis-based strategies are actively being explored in cancer therapy.

Who was reviewed?

Because this was a review-style commentary, it synthesized evidence across cell and animal models and translational human observations reported in the highlighted study. The core experimental systems included two-dimensional cancer cell lines, three-dimensional tumor spheroids, and xenograft mouse models, alongside additional colorectal cancer mouse models used to test microbial effects in vivo. It also referenced human fecal and tissue findings that connect microbiome metabolites and host pathways to colorectal cancer, and it contrasted pro-tumor and anti-tumor microbial metabolite examples shown in the figure, including immune-supportive indole derivatives from Lactobacillus.

What were the most important findings?

The key message was that IDA uniquely suppresses ferroptosis in colorectal cancer cells through signaling rather than by simply lowering lipid peroxidation. A broad metabolite screen identified IDA as a strong inhibitor of RSL3-triggered ferroptosis, while other tryptophan derivatives did not show the same effect. Mechanistically, IDA acted as an endogenous ligand for AHR, drove AHR nuclear activity, and required intact AHR function to block ferroptosis. Downstream, the pathway ran through AHR-driven ALDH1A3 induction, which increased NADH availability to support FSP1-dependent CoQ10 reduction, strengthening anti-ferroptotic defense in a way that is described as GPX4-independent. In translational observations, IDA levels were higher in colorectal cancer–associated fecal profiles, Peptostreptococcus anaerobius appeared as a major in vivo contributor to IDA biosynthesis, and tumor samples showed higher AHR and ALDH1A3 expression, supporting relevance to human disease context.

What are the greatest implications of this study/ review?

This review expands how clinicians and researchers should interpret “microbiome effects” in colorectal cancer: microbial metabolites can promote cancer not only through inflammation or immune shifts, but also by actively protecting tumor cells from ferroptosis. It suggests a functional microbiome signature where P. anaerobius–linked IDA production aligns with an AHR–ALDH1A3–FSP1–CoQ10 anti-ferroptosis axis, potentially making tumors harder to eliminate with ferroptosis-inducing strategies. Clinically, it encourages combining ferroptosis-targeted therapies with approaches that disrupt this metabolite-driven protection, while also reminding teams to consider the additive and competing effects of multiple metabolites and diet-driven microbiome changes when predicting tumor behavior and treatment response.