# p53 and fatty acids collaborate to trigger ferroptosis via the FBXO2-FABP5 axis in colorectal cancer

## TL;DR

This study shows that p53 and fatty acids work together to trigger cell death in colorectal cancer through a specific pathway.

## Contribution

The study identifies a new mechanism by which p53 and fatty acids induce ferroptosis in colorectal cancer.

## Key findings

- p53 induces ferroptosis when polyunsaturated fatty acids are abundant.
- FBXO2 interacts with FABP5 to reduce PUFA levels and increase ferroptosis resistance.
- Arachidonic acid supplementation reverses resistance and promotes ferroptosis in CRC cells.

## Abstract

In colorectal cancer (CRC), p53 can either suppress or potentiate tumor sensitivity to ferroptosis under oxidative stress conditions. However, it remains to be elucidated how p53 differentially regulates ferroptosis, and whether it can initiate ferroptosis. Our findings reveal that p53 induces ferroptosis in the presence of abundant polyunsaturated fatty acids (PUFAs). FBXO2, which is encoded by a p53-inducible target gene, interacts with FABP5 and promotes the lysosomal degradation of FABP5 through chaperone-mediated autophagy. This results in a decrease in the levels of PUFAs, thereby increasing resistance to ferroptosis in CRC. Notably, the supplementation of arachidonic acid not only reverses p53-mediated ferroptosis resistance, but also coordinates with p53 to initiate ferroptosis independently of additional oxidative stress, effectively suppressing the growth of CRC cells both in vitro and in vivo. Altogether, our study uncovers that the availability of PUFAs is crucial for p53 to exert a pro-ferroptotic function in CRC.