A novel taxane SB-T-101141 triggers a noncanonical ferroptosis to overcome Paclitaxel resistance of breast cancer via iron homeostasis-related KHSRP.

Acquired multidrug resistance impedes the clinical application of paclitaxel. Here, we disclosed that the taxane SB-T-101141 efficiently contributed to a novel ferroptosis-like cell death of Paclitaxel-resistant and parental breast cancer cells. Functionally, SB-T-101141 facilitated the production of iron and ferrous ions along with reactive oxygen species (ROS), composed of lipid ROS and lipid peroxidation-derived aldehydes, including malonaldehyde (MDA), and glutathione (GSH) depletion. Iron chelators and ROS scavengers significantly attenuated cell death, and the inorganic ROS rendered by SB-T-101141. However, the ferroptosis-associated lipid oxide inhibitors could not block the lipid ROS and cell death triggered by SB-T-101141. Meanwhile, via genome-scale CRISPR-Cas9 screening, we uncovered that SB-T-101141 bound to the KH-type splicing regulatory protein (KHSRP) to inhibit the iron-dependent expression of CDGSH iron sulfur domain 1 (CISD1) associated with iron homeostasis, which consequently led to a novel type of ferroptosis of breast tumors. Moreover, RNA deep sequencing indicated that SB-T-101141 synergistically enhanced the iron-dependent activation of JNK and PERK pathways via KHSRP. Altogether, our results here demonstrate the potential clinical application of SB-T-101141 as a novel ferroptosis inducer in Paclitaxel-resistant breast cancer treatment.