Dual ferroptosis induction in N2-TANs and TNBC cells via FTH1 targeting: A therapeutic strategy for triple-negative breast cancer

  • Cell Rep Med. 2025 Jan 21;6(1):101915. doi: 10.1016/j.xcrm.2024.101915.
Yichen Liu  1 ,  Qingyan Sun  2 ,  Jingwen Guo  2 ,  Li Yan  3 ,  Yue Yan  1 ,  Yiting Gong  1 ,  Jiayi Lin  1 ,  Hu Yuan  1 ,  Jinmei Jin  1 ,  Bei Wang  1 ,  Hongzhuan Chen  1 ,  Lijun Zhang  4 ,  Weidong Zhang  5 ,  Xin Luan  6
Affiliations
  • 1. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2. National Key Laboratory of Lead Druggability Research (Shanghai Institute of Pharmaceutical Industry Co. Ltd., China State Institute of Pharmaceutical Industry Co. Ltd.), Shanghai 200040, China.
  • 3. School of Pharmacy, Naval Medical University, Shanghai 200433, China.
  • 4. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
  • 5. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; School of Pharmacy, Naval Medical University, Shanghai 200433, China; Institute of Medicinal Plant Development, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100193, China. Electronic address: [email protected].
  • 6. Shanghai Frontiers Science Center of TCM Chemical Biology, Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China. Electronic address: [email protected].
PMID: 39809268 DOI: 10.1016/j.xcrm.2024.101915
Abstract

Tumor-associated neutrophils (TANs) play a critical role in the progression and prognosis of triple-negative breast Cancer (TNBC), with N2-type TANs known for their pro-tumor characteristics. This study introduces CT-1, a derivative of cryptotanshinone that effectively suppresses TNBC growth while selectively reducing the proportion of N2-type TANs within tumor tissue. Notably, CT-1 induces simultaneous Ferroptosis in both N2-type TANs and TNBC cells, a dual mechanism that enhances its therapeutic efficacy. The study identifies ferritin heavy chain 1 (FTH1), a key protein in iron metabolism, as the direct target of CT-1. By targeting FTH1, CT-1 facilitates the interaction between NCOA4 and ferritin, triggering ferritinophagy-mediated Ferroptosis. These findings position CT-1 as a promising therapeutic agent, offering a strategy to combat TNBC by inducing Ferroptosis in both N2-type TANs and Cancer cells. This approach underscores the potential of FTH1 as a therapeutic target for treating TNBC.

Keywords
FTH1; N2-type tumor-associated neutrophils; TNBC; cryptotanshinone derivative; ferroptosis.
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