The drug-resistant colorectal cancer organoids exhibit elevated LGR4 expression and Wnt signaling activation, which confer resistance by upregulating SLC7A11 to inhibit ferroptosis. Targeting LGR4 with a monoclonal antibody (LGR4-mAb) sensitizes cancer cells to chemotherapy-induced ferroptosis. Here, SLC7A11 is linked to colorectal cancer.