2. Academic Validation
  3. Arenobufagin induces ferroptosis in gastric cancer stem cells via the HCAR1-GPX4/SLC7A11 antioxidant axis

Arenobufagin induces ferroptosis in gastric cancer stem cells via the HCAR1-GPX4/SLC7A11 antioxidant axis

  • Eur J Pharmacol. 2026 Apr 10:1020:178785. doi: 10.1016/j.ejphar.2026.178785.
Hainan Wang 1,  Ning Wang 2,  Wei Gu 3,  Manman Wang 1,  Hui Cheng 2,  Shiming He 4,  Meng Wang 5,  Qinglin Li 6
Affiliations

Affiliations

  • 1 College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, 230038, China.
  • 2 Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, 230038, China.
  • 3 Department of Biochemistry and Molecular Biology, School of Laboratory Medicine, and Anhui Provincial Key Laboratory of Tumor Evolution and Intelligent Diagnosis and Treatment, Bengbu Medical University, 2600 Donghai Avenue, Bengbu, Anhui, 233030, China.
  • 4 College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China. Electronic address: [email protected].
  • 5 College of Integrated Chinese and Western Medicine, Anhui University of Chinese Medicine, Hefei, Anhui, 230012, China; Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, 230038, China; Anhui Huarun Jinchan Pharmaceutical Co., Ltd., Huaibei, Anhui, 235000, China. Electronic address: [email protected].
  • 6 Key Laboratory of Xin'an Medicine, Ministry of Education, Anhui University of Chinese Medicine, Hefei, Anhui, 230038, China; Bozhou Vocational and Technical College, Bozhou, Anhui, 236800, China. Electronic address: [email protected].
PMID: 41856196 DOI: 10.1016/j.ejphar.2026.178785
Abstract

Arenobufagin (ARBU), a steroid compound extracted from the venom of Bufo gargarizans, exhibits multi-target pharmacological activities, yet its role in regulating Ferroptosis in gastric Cancer Stem Cells (GCSCs) remains unclear. This study systematically evaluated the antitumor effects and mechanisms of ARBU using in vitro sphere culture, Organoid models, and xenografts. ARBU inhibited GCSC proliferation and sphere formation in a concentration-dependent manner, reduced EdU incorporation and SOX2 expression in organoids, and markedly suppressed tumor growth in vivo while downregulating SOX2 and Nanog, with favorable biosafety. Mechanistically, ARBU induced Ferroptosis, evidenced by elevated MDA, ROS, and Fe2+, decreased GSH and SOD, mitochondrial damage, COX2 upregulation, and GPX4/SLC7A11 downregulation. RNA-seq and functional studies further revealed that HCAR1 critically regulates GCSC self-renewal and antioxidant defense, and ARBU promoted Ferroptosis via HCAR1 suppression. Collectively, these results demonstrate that ARBU inhibits GCSC proliferation and stemness by inducing Ferroptosis through downregulation of the HCAR1 pathway, highlighting its potential as a therapeutic candidate for gastric Cancer.

Keywords

Arenobufagin; Ferroptosis; Gastric cancer stem cells; HCAR1.

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