The vitamin B2 (riboflavin) must be absorbed through diet: it can be found in dairy products, eggs, meat, and green vegetables. The body’s metabolism converts vitamin B2 into molecules that protect the cell from oxidative damage. Now, a CRISPR–Cas9 screen has uncovered vitamin B2 as a modulator of ferroptosis sensitivity: it supports the stability of ferroptosis suppressor protein 1 (FSP1) and the recycling of lipid-soluble antioxidants, thereby mitigating phospholipid peroxidation. One outcome of this process may be that vitamin B2 also protects cancer cells.
“Vitamin B2 plays a crucial role in protecting cancer cells from ferroptosis, a special form of programmed cell death,” said Vera Skafar, a PhD student who is a member of the research group led by José Pedro Friedmann Angeli, PhD, professor of translational cell biology at the Rudolf Virchow Centre (RVZ) at Julius-Maximilians-Universität Würzburg (JMU).
This work is published in Nature Cell Biology in the paper, “Riboflavin metabolism shapes FSP1-driven ferroptosis resistance.”
The body uses programmed cell death to allow damaged or dangerous cells to die in a controlled manner without causing inflammation in the surrounding tissue. Specifically, ferroptosis is associated with many pathological conditions, including cancer and neurodegeneration.
Unlike other cell-death pathways, ferroptosis is triggered when iron-driven lipid peroxidation overwhelms a cell’s antioxidant protection. Cancer cells often evade ferroptosis by boosting redox defense systems. This study highlights vitamin B2 metabolism as an important contributor to those defenses, implying that targeting riboflavin-derived cofactors could weaken ferroptosis resistance and make tumors more vulnerable.
The protein FSP1 is among the components responsible for protecting healthy cells from cell death. Vitamin B2 supports the protein in this task; the researchers observed that a deficiency of the vitamin made cancer cells more susceptible to ferroptosis.
It could be possible to utilize this therapeutically. Switching off the metabolic pathway of vitamin B2 and thus specifically triggering the death of cancer cells. “However, an inhibitor that can do this is still missing,” said Skafar. The researchers addressed this limitation by employing roseoflavin, a natural compound with a structure like vitamin B2 and produced by bacteria.
The team tested the active substance in cancer cell models, and roseoflavin triggered ferroptosis in low concentrations. The study paves the way for the development of targeted cancer therapies based on ferroptosis. In the next step, the RVZ working group will focus on developing inhibitors of vitamin B2 metabolism; the aim will be to evaluate their use in preclinical cancer models.
“Ferroptosis is not only relevant to cancer,” noted Angeli. “Increasing evidence suggests that it also contributes to pathological processes in neurodegenerative diseases and in tissue damage following organ transplantation or ischemia-reperfusion injury.” Understanding how vitamin B2 metabolism influences ferroptosis may therefore have broader implications for diseases in which excessive or insufficient ferroptosis is implicated.
