2. Academic Validation
  3. Inhibitory effect of blestriarene C on triple-negative breast cancer: Inducing ferroptosis and mitophagy via SESN2/AKT/FOXO4 axis

Inhibitory effect of blestriarene C on triple-negative breast cancer: Inducing ferroptosis and mitophagy via SESN2/AKT/FOXO4 axis

  • Chin Med J (Engl). 2026 Mar 5;139(5):699-709. doi: 10.1097/CM9.0000000000003960.
Junsha An 1 2,  Pingting Chen 1,  Mingyu Han 1,  Heng Zhang 1,  Yajie Lu 1,  Hailin Tang 3,  Qian Bi 4,  Weiwei Pan 5,  Cheng Peng 2,  Zhaokai Zhou 6,  Fu Peng 1
Affiliations

Affiliations

  • 1 Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan 610041, China.
  • 2 Department of Pharmacology, State Key Laboratory of Southwestern Chinese Medicine Resources, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China.
  • 3 Department of Experimental Research, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou, Guangdong 510060, China.
  • 4 Department of Radiation Oncology, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100730, China.
  • 5 Department of Cell Biology, College of Medicine, Jiaxing University, Jiaxing, Zhejiang 314001, China.
  • 6 Department of Urology, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
PMID: 41527177 DOI: 10.1097/CM9.0000000000003960
Abstract

Background: Triple-negative breast Cancer (TNBC) is a highly aggressive and treatment-resistant subtype of breast Cancer, characterized by high rates of metastasis and mortality. This study aimed to identify and evaluate the therapeutic potential of blestriarene C (BC), a novel diphenanthrene compound, in the treatment of TNBC. The study also sought to explore the underlying mechanisms and signaling pathways involved in BC's antitumor effects.

Methods: A multiomics analysis was conducted to identify key genes and pathways involved in TNBC treatment. We performed experiments related to cell viability, Ferroptosis, and Mitophagy to explore the effects of BC in the treatment of TNBC, utilizing the TNBC cell lines BT-549 and 4T1 cells. The impact of sestrin 2 (SESN2) knockout on BC's effects was also studied. We also conducted in vivo experiments using the patient-derived xenograft (PDX) model in zebrafish to assess the antitumor effects of BC.

Results: The results of RNA Sequencing and proteomics showed that Ferroptosis and Mitophagy may be the main mechanisms of BC acting on TNBC cells. BC could inhibit cell proliferation by modulating the phosphoinositide 3-kinase/protein kinase B/forkhead box O4 and SESN2/mechanistic target of rapamycin signaling pathways, and inducing Ferroptosis and Mitophagy. SESN2 and microtubule-associated protein 1 light chain 3 beta (MAP1LC3B), as hub genes, participated in regulating the therapeutic effect of BC on TNBC. TNBC tumors in zebrafish treated with BC were smaller and lighter, indicating that BC had antitumor effect.

Conclusions: BC emerges as a promising therapeutic agent for TNBC by targeting SESN2 and MAP1LC3B, modulating associated signaling pathways, and inducing Ferroptosis and Mitophagy. These findings provide the basis for further investigation of BC's potential as a targeted therapy for TNBC.

Keywords

Blestriarene C; Ferroptosis; Mitophagy; Sestrin 2; Triple-negative breast cancer.

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