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Lipid peroxidation triggers ferroptosis, a type of regulated cell death that is iron-dependent. Owing to its important role in tumor suppression, ferroptosis represents an extremely promising therapeutic target for cancer. QD394, a quinazolinone-based compound, was recently identified as a novel redox regulator with demonstrated cytotoxic and proapoptotic effects in pancreatic and breast cancer models. Preliminary RNA sequencing analysis suggested potential associations between QD394 treatment and ferroptosis, mitogen-activated protein kinase (MAPK) signaling, and angiogenic pathways. Cell Counting Kit-8 (CCK-8), colony formation assay, and 5-ethynyl-2'-deoxyuridine (EdU) assays, as well as annexin V/PI staining, revealed that QD394 inhibited cell proliferation and induced apoptosis. Microtubule assembly, chick chorioallantoic membrane (CAM), and scratch assays demonstrated that QD394 suppressed angiogenesis. Notably, QD394-treated colorectal cancer (CRC) cells exhibited decreased levels of glutathione (GSH), solute carrier family 7 member 11 (xCT), and glutathione peroxidase 4 (GPX4), and increased levels of malondialdehyde (MDA) and lipid reactive oxygen species (ROS), suggesting that QD394 induces ferroptosis. Mechanistically, QD394 treatment reduced specific protein 1 (SP1) levels through ubiquitin-mediated proteolysis. Notably, overexpression of SP1 counteracted QD394-induced ferroptosis. Moreover, QD394 treatment significantly increased the ratio of p-JNK to total JNK in CRC cells, whereas SP1 overexpression effectively reversed this effect. In a xenograft model, QD394 significantly inhibited tumor growth and decreased tumor weight, and the expression of Ki-67, GPX4, and SP1. In contrast, 4-hydroxynonenal (4-HNE) and p-JNK levels were markedly elevated. Collectively, our findings reveal that QD394 triggers ferroptosis in CRC through the SP1/JNK signaling axis, highlighting its potential as a novel anticancer agent.