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

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.