<p>The mechanism of ferroptosis propagation is still unclear. Here our results indicate that the cells undergoing ferroptosis secrete Galectin-13, which binds to CD44 and inhibits the plasma membrane localization of SLC7A11 in neighboring cells, thereby accelerating neighboring cell death and promoting ferroptosis propagation. FOXK1 was phosphorylated by PKCβII and then facilitated the expression and secretion of Galectin-13 during ferroptotic cell death. Correlation analysis and functional analysis revealed that ferroptosis propagation ability was a previously unrecognized determinant of ferroptosis sensitivity in human cancer cells. A synthetic Galectin-13 mimetic peptide was shown to strongly enhance the sensitivity of tumors to the imidazole ketone erastin, radiotherapy and immunotherapy by boosting ferroptosis. In particular, cancer stem cells were vulnerable to the combination of Galectin-13 mimetic peptide and ferroptosis inducers. Our study provides new insights into ferroptosis propagation and highlights novel strategies for targeting ferroptosis to treat tumors.</p><p></p>