Ferroptosis: principles and significance in health and disease Original paper

What was reviewed?

This paper reviewed ferroptosis as a regulated, non-apoptotic form of cell death driven by iron-dependent lipid peroxidation, then mapped the main molecular “pressure points” that determine whether cells resist or enter ferroptosis. It focused on core chemistry (iron handling and lipid oxidation), the best-supported defense systems that stop membrane damage, and how organelles and metabolism shape susceptibility. It also summarized where ferroptosis matters in disease, with emphasis on cancer biology and therapy response, and it highlighted emerging clinical angles such as candidate biomarkers and drug strategies to either trigger ferroptosis in tumors or block it in tissue injury.

Who was reviewed?

Because this is a review, it did not study a single patient cohort. Instead, it synthesized evidence across experimental systems that include human and mouse cells, tumor models, and inflammatory or ischemia–reperfusion models, alongside translational observations in conditions where iron load and oxidized lipids rise. It also integrated host–microbe work showing that gut and intratumoral microbes can shift ferroptosis sensitivity through secreted metabolites, linking microbiome composition to host redox control in contexts such as colorectal cancer, infection-driven inflammation, and barrier injury.

What were the most important findings?

The review clarified that ferroptosis starts when iron availability and oxidant generation outpace antioxidant “brakes,” leading to runaway oxidation of polyunsaturated lipids and, later, loss of membrane integrity. It emphasized the central protective role of the cystine import pathway that fuels glutathione and GPX4 activity, and it highlighted parallel protection that does not rely on GPX4, including membrane-associated systems that regenerate radical-trapping antioxidants. It connected lipid remodeling enzymes to risk, explained how iron trafficking and ferritin turnover can raise the labile iron pool, and described membrane damage control mechanisms that influence whether death spreads to neighboring cells. Importantly for microbiome signatures, it described microbial and metabolite links that can suppress or reshape ferroptosis programs, including colorectal cancer–relevant anaerobes and Lactobacillus-derived activities that modulate host antioxidant pathways.

What are the greatest implications of this review?

For clinicians, the key implication is that ferroptosis is not just a lab concept: it is a tunable vulnerability in cancer and a plausible driver of injury in organs exposed to oxidative stress, ischemia–reperfusion, infection, and chronic inflammation. The review supports a practical framework: push ferroptosis in tumors that resist apoptosis, but prevent ferroptosis in settings like acute tissue injury where lipid peroxidation amplifies damage. It also suggests that biomarkers tied to oxidized lipids and iron handling may help stratify risk or treatment response, while microbiome-aware care may matter because microbial metabolites can shift host ferroptosis thresholds and potentially influence colorectal cancer biology and therapy response.