Mori Folium ethanol extracts induce ferroptosis and suppress gastric cancer progression by inhibiting the AKT/GSK3β/NRF2 axis

  • Phytomedicine. 2025 Jul:142:156789. doi: 10.1016/j.phymed.2025.156789.
Xin Hu  1 ,  Hongbo Chang  1 ,  Yan Guo  1 ,  Lang Yu  2 ,  Jing Li  2 ,  Bili Zhang  3 ,  Hui Zhao  4 ,  Jingyang Xu  2 ,  Guangzhao Pan  5 ,  Kui Zhang  2 ,  Muhan Lü  6 ,  Hongjuan Cui  7
Affiliations
  • 1. State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China; Jinfeng Laboratory, Chongqing 401329, China.
  • 2. State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China.
  • 3. School of Life Science, Chongqing University, Chongqing 400044, China.
  • 4. Key Laboratory for Regenerative Medicine, Ministry of Education, School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong SAR, China.
  • 5. Center for Innovative Drug Research, Hangzhou Institute of Medicine (HIM), Chinese Academy of Sciences, Hangzhou, Zhejiang 310018, China. Electronic address: [email protected].
  • 6. Department of Gastroenterology, The Affiliated Hospital of Southwest Medical University, Luzhou, 646000, China. Electronic address: [email protected].
  • 7. State Key Laboratory of Resource Insects, Medical Research Institute, Southwest University, Chongqing 400715, China; Jinfeng Laboratory, Chongqing 401329, China. Electronic address: [email protected].
PMID: 40344847 DOI: 10.1016/j.phymed.2025.156789
Abstract

Background: Mori Folium, the leaf of Morus alba L., is a traditional Chinese medicine (TCM) known for its diverse pharmacological activities, including anti-inflammatory and immunomodulatory effects. While the Morus alba itself has been reported to contain various bioactive compounds with Anticancer properties, the Anticancer activity of Mori Folium and its underlying mechanisms remain insufficiently understood.

Purpose: This study aimed to investigate the effects of Mori Folium ethanol extracts (MFEE) on gastric Cancer (GC) and to elucidate its underlying mechanisms.

Methods: To investigate the anti-GC properties of MFEE, CCK-8, colony formation, EdU, flow cytometry, and soft agar, scratch, and transwell assays were employed. Western blot was employed to analyze the expression of ferroptotic proteins, while ferroptotic cellular events were also assessed, including iron accumulation, GSH levels, Reactive Oxygen Species (ROS) production, mitochondrial changes, and lipid peroxidation. The chemical profile of MFEE was characterized using a UPLC-ESI-MS/MS system. Additionally, network pharmacology analysis was performed to investigate the potential anti-GC mechanisms of MFEE. Finally, the in vivo anti-cancer effects of MFEE were evaluated using a subcutaneous mouse model, with hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining to assess histopathological and molecular changes.

Results: This study demonstrated that MFEE suppresses GC cell proliferation, blocks the G1-S cell cycle transition, and inhibits migration and invasion by promoting Fe²⁺ accumulation, increasing MDA levels and ROS, depleting GSH, and downregulating the expression of xCT and GPX4, thereby inducing Ferroptosis. Chemical analysis identified 1596 phytochemicals, including 35 bioactive compounds. The induction of Ferroptosis by MFEE was associated with the inhibition of the PI3K/Akt signaling pathway, modulating the Akt/GSK3β/NRF2 axis. Activation of Akt by SC79 was found to mitigate MF-induced Ferroptosis. Notably, MFEE enhanced the chemosensitivity of GC cells to cisplatin, potentially through Ferroptosis induction.

Conclusion: This study revealed that MFEE induces Ferroptosis in GC cells by modulating the PI3K/Akt signaling pathway, enhancing chemosensitivity to cisplatin, and providing a potential therapeutic strategy for GC.

Keywords
Chemosensitivity; Ferroptosis; Gastric cancer; Mori Folium; PI3K/AKT Signaling Pathway.
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