Momordin Ic targets SREBP1 to disrupt lipid homeostasis and trigger synergistic apoptosis-ferroptosis in triple-negative breast cancer

  • Phytomedicine. 2026 Jun:155:158190. doi: 10.1016/j.phymed.2026.158190.
Yao Cheng  1 ,  Yu-Zhe Shi  2 ,  Jia-Yi Zheng  1 ,  Yu-Bing Liu  1 ,  Yi-Tong Chen  3 ,  Jing-Xia Bao  2 ,  Xiao-Yu He  2 ,  Jun-Qu Chen  2 ,  Quan Li  1 ,  Xuan-Xuan Dai  4
Affiliations
  • 1. Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, China.
  • 2. Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, China; Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China.
  • 3. Department of Medical Administration, Wenzhou Central Hospital, Wenzhou, Zhejiang 325015, China.
  • 4. Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang 325015, China; Key Laboratory of Clinical Laboratory Diagnostics (Ministry of Education), The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325015, China. Electronic address: [email protected].
PMID: 42008854 DOI: 10.1016/j.phymed.2026.158190
Abstract

Background: Triple-negative breast Cancer (TNBC) constitutes a clinically challenging disease subtype characterized by high metastatic potential and unsatisfactory treatment outcomes. Developing innovative pharmacological interventions is therefore critically important. The plant-derived compound Momordin Ic (MMD) has demonstrated preliminary anti-neoplastic activity; however, its therapeutic potential against TNBC and corresponding mechanisms require systematic investigation.

Purpose: This study aims to systematically investigate the therapeutic potential and underlying mechanisms of MMD against triple-negative breast Cancer.

Methods: MTT, EdU, colony formation, wound healing, transwell, flow cytometry, and xenograft mouse models. Mechanisms were explored using transcriptomic Sequencing, molecular docking, cellular thermal shift assay (CETSA), and western blotting.

Results: MMD substantially suppressed the growth, movement, and infiltration of TNBC cells, led to G2/M phase blockade and induced mitochondrial Apoptosis together with Ferroptosis. Mechanistically, MMD was found to directly bind to the transcription factor sterol regulatory element-binding protein 1 (SREBP1), suppressing its activity and downstream lipogenic genes (e.g. ACC1, SCD1). This led to disrupted lipid homeostasis, evidenced by reduced neutral lipid droplets and total Cholesterol. Overexpression of SREBP1 partially reversed the anti-tumor effects of MMD. Furthermore, MMD robustly suppressed tumor growth in a xenograft model without observable toxicity.

Conclusions: Our findings indicate that MMD produces anti-TNBC responses through engagement of SREBP1 as a key functional mediator, causing metabolic disturbance and coordinated activation of apoptotic and ferroptotic pathways. These findings suggest that MMD could be further explored as a treatment candidate and highlight the SREBP1 pathway as a valuable target for TNBC treatment.

Keywords
Apoptosis; Ferroptosis; Lipid metabolism; MMD; SREBP1; Triple-negative breast cancer.
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