2. Academic Validation
  3. SLC6A8-mediated creatine uptake suppresses ERK2-FSP1 signaling and induces ferroptosis in colorectal cancer

SLC6A8-mediated creatine uptake suppresses ERK2-FSP1 signaling and induces ferroptosis in colorectal cancer

  • Cell Rep. 2025 Sep 23;44(9):116139. doi: 10.1016/j.celrep.2025.116139.
Xiaojun Zhou 1,  Genxin Wang 1,  Yuhang Wu 1,  Mingzhi Wu 1,  Xiang Zhai 2,  Chenhui Tian 1,  Edward V Prochownik 3,  Congqing Jiang 4,  Youjun Li 5
Affiliations

Affiliations

  • 1 Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei, China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan 430071, China.
  • 2 Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei, China.
  • 3 Division of Hematology/Oncology, Children's Hospital of Pittsburgh of UPMC, Department of Microbiology and Molecular Genetics, Pittsburgh Liver Research Center and Hillman Cancer Center, University of Pittsburgh Medical Center, Pittsburgh, PA 15224, USA.
  • 4 Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei, China. Electronic address: wb002554@whu.edu.cn.
  • 5 Department of Colorectal and Anal Surgery, Zhongnan Hospital of Wuhan University, Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Wuhan University, Wuhan 430072, Hubei, China; Frontier Science Center for Immunology and Metabolism, Medical Research Institute, Wuhan University, Wuhan 430071, China. Electronic address: liy7@whu.edu.cn.
PMID: 40892544 DOI: 10.1016/j.celrep.2025.116139
Abstract

Tumor metabolic reprogramming is critical for providing energy to support proliferation and resistance to stress-induced cell death. However, the regulatory mechanisms linking these processes remain incompletely understood. Here, using untargeted metabolomics, we demonstrate that creatine potently induces Ferroptosis in colorectal Cancer (CRC). Mechanistically, creatine binds extracellular signal-regulated kinase 2 (ERK2), impairing its activation by mitogen-activated protein kinase kinase 1 (MEK1). Inhibiting the creatine transporter SLC6A8 reduces creatine uptake and activates ERK2. Activated ERK2 then binds, phosphorylates Ferroptosis suppressor protein 1 (FSP1) at Thr109, and stabilizes it to inhibit Ferroptosis. Creatine supplementation suppresses tumor growth, enhances CD8+ T cell infiltration, and sensitizes tumors to anti-programmed cell death protein 1 (PD-1) immunotherapy. Our study identifies ERK2 as a creatine sensor regulating FSP1 stability and Ferroptosis resistance, highlighting the therapeutic potential of creatine supplementation in combination Cancer Immunotherapy.

Keywords

CP: Cancer; CP: Metabolism; creatine; ferroptosis; mmune checkpoint blockade; tumor metabolic reprogramming.

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