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

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

  • Cell Death Dis. 2025 May 19;16(1):403. doi: 10.1038/s41419-025-07710-0.
Xiaomei Zhang # 1 2 3,  Ying Fang # 3,  Dade Rong # 3 4,  Jie Li 5,  Zhe Li 3,  Huidan Qiu 3,  Qiuxia Chen 1,  Jing Yang 3,  Changwei Wang 6,  Junxiu Huang 3,  Qin Zhao 5,  Shulan Yang 7,  Haihe Wang 8 9
Affiliations

Affiliations

  • 1 Centre for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 2 Institute of Precision Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 3 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China.
  • 4 Faculty of Health Sciences, University of Macau, Taipa, Macau, China.
  • 5 Engineering Research Center of Tibetan Medicine Detection Technology, School of Medicine, Xizang Minzu University, Xianyang, China.
  • 6 Guangzhou Institutes of Biomedicine and Health, Chinese Academy of Sciences, Guangzhou, Guangdong, China.
  • 7 Centre for Translational Medicine, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China. yangshl3@mail.sysu.edu.cn.
  • 8 Department of Biochemistry, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, Guangdong, China. wanghaih@mail.sysu.edu.cn.
  • 9 Clinical Medical Research Centre for Plateau Gastroenterological Diseases of Xizang Autonomous Region, Xizang Minzu University, Xianyang, China. wanghaih@mail.sysu.edu.cn.
  • # Contributed equally.
PMID: 40389408 DOI: 10.1038/s41419-025-07710-0
Abstract

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.

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