A Novel Taxane Sbt101141 Triggers A Noncanonical Ferroptosis To Overcome Paclitaxel Resistance Of Breast Cancer Via Iron Homeostasisrelated Khsrp Xiaomei Zhang Ying Fang Dade Rong Jie Li Zhe Li Huidan Qiu Qiuxia Chen Jing Yang Changwei Wang Junxiu Huang Qin Zhao Shulan Yang Haihe Wang by Xiaomei Zhang & Ying Fang & Dade Rong & Jie Li & Zhe Li & Huidan Qiu & Qiuxia Chen & Jing Yang & Changwei Wang & Junxiu Huang & Qin Zhao & Shulan Yang & Haihe Wang instant download after payment.

Acquired multidrug resistance impedes the clinical application of paclitaxel. Here, we disclosed that the taxane SB-T-101141efficiently 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 ROSand lipid peroxidation-derived aldehydes, including malonaldehyde (MDA), and glutathione (GSH) depletion. Iron chelators andROS scavengers significantly attenuated cell death, and the inorganic ROS rendered by SB-T-101141. However, the ferroptosis1234567890();,:associated lipid oxide inhibitors could not block the lipid ROS and cell death triggered by SB-T-101141. Meanwhile, via genomescale CRISPR-Cas9 screening, we uncovered that SB-T-101141 bound to the KH-type splicing regulatory protein (KHSRP) to inhibitthe iron-dependent expression of CDGSH iron sulfur domain 1 (CISD1) associated with iron homeostasis, which consequently led toa novel type of ferroptosis of breast tumors. Moreover, RNA deep sequencing indicated that SB-T-101141 synergistically enhancedthe iron-dependent activation of JNK and PERK pathways via KHSRP. Altogether, our results here demonstrate the potential clinicalapplication of SB-T-101141 as a novel ferroptosis inducer in Paclitaxel-resistant breast cancer treatment.Cell Death and Disease (2025) 16:403 ;