SLC6A8-mediated creatine uptake suppressesERK2-FSP1 signaling and induces ferroptosis incolorectal cancer by Xiaojun Zhou & Genxin Wang & Yuhang Wu & Mingzhi Wu & Xiang Zhai & Chenhui Tian & Edward V. Prochownik & Congqing Jiang & Youjun Li instant download

SLC6A8-mediated creatine uptake suppressesERK2-FSP1 signaling and induces ferroptosis incolorectal cancer by Xiaojun Zhou & Genxin Wang & Yuhang Wu & Mingzhi Wu & Xiang Zhai & Chenhui Tian & Edward V. Prochownik & Congqing Jiang & Youjun Li instant download

SUMMARYTumor metabolic reprogramming is critical for providing energy to support proliferation and resistance tostress-induced cell death. However, the regulatory mechanisms linking these processes remain incompletelyunderstood. 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, phosphorylatesferroptosis 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-programmedcell death protein 1 (PD-1) immunotherapy. Our study identifies ERK2 as a creatine sensor regulating FSP1stability and ferroptosis resistance, highlighting the therapeutic potential of creatine supplementation incombination cancer immunotherapy.