2. Academic Validation
  3. p53 and fatty acids collaborate to trigger ferroptosis via the FBXO2-FABP5 axis in colorectal cancer

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

  • Redox Biol. 2026 Mar:90:104043. doi: 10.1016/j.redox.2026.104043.
Jing Tong 1,  Tao Han 2,  Jun Deng 3,  Yu Gan 1,  Ruiwen Ruan 3,  Wei Zhao 1,  Chen Xiong 1,  Quan Liao 1,  Shiqi Chen 1,  Huitong Bu 2,  Jianping Xiong 3,  Xiang Zhou 4,  Qian Hao 5
Affiliations

Affiliations

  • 1 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
  • 2 Xinxiang Key laboratory for Molecular Oncology, Institutes of Health Central Plains, Henan Medical University, Xinxiang, 453003, China.
  • 3 Department of Oncology, The First Affiliated Hospital, Jiangxi Medical College, Nanchang University, Nanchang, Jiangxi, 330006, China; Jiangxi Key Laboratory for Individual Cancer Therapy, Nanchang, Jiangxi, 330006, China.
  • 4 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China; Key Laboratory of Breast Cancer in Shanghai, Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, 200032, China. Electronic address: [email protected].
  • 5 Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai, 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China. Electronic address: [email protected].
PMID: 41604941 DOI: 10.1016/j.redox.2026.104043
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.

Keywords

Cancer therapy; Chaperone-mediated autophagy (CMA); Ferroptosis; Polyunsaturated fatty acid (PUFA); p53.

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