Artemisitene triggers calcium-dependent ferroptosis by disrupting the LSH-EWSR1 interaction in colorectal cancer

Colorectal cancer (CRC), propelled by extreme molecular heterogeneity and intractable drug resistance, is rapidly becoming a global health challenge. Ferroptosis offers a promising therapeutic strategy by exploiting the iron addiction and oxidative vulnerability of CRC cells. However, available methods to trigger ferroptosis are still limited, mostly focusing on antioxidant systems or iron metabolism. Here, we found that artemisitene (ATT), a bioactive natural sesquiterpene isolated from Artemisia annua, acted as a CRC therapeutic agent by promoting calcium-dependent ferroptosis. Integrative transcriptomics revealed that ATT repressed cytochrome P450 family 24 subfamily A member 1 (CYP24A1) expression, the pivotal mediator of this response. The ensuing calcium overload downregulated stearoyl-CoA desaturase (SCD) by CAMKK2/AMPK/SREBF1 axis, enriching oxidizable fatty acids and sensitizing CRC cells to lethal lipid peroxidation. Mechanistically, ATT was found to directly target lymphoid-specific helicase (LSH), covalently binding to the Cys205 residue of LSH and thereby disrupting its interaction with EWS RNA binding protein 1 (EWSR1). This disruption ultimately suppressed CYP24A1 transcription. Our findings revealed that pharmacological blockade of the LSH/CYP24A1/SCD axis triggers calcium-driven ferroptosis, positioning ATT as a potent, mechanism-based therapeutic for CRC.