2. Academic Validation
  3. Phytosphingosine suppresses gastric cancer through SFRP4/β-catenin axis-mediated Wnt signaling pathway inhibition

Phytosphingosine suppresses gastric cancer through SFRP4/β-catenin axis-mediated Wnt signaling pathway inhibition

  • Chem Biol Interact. 2025 Sep 20:421:111749. doi: 10.1016/j.cbi.2025.111749.
Yanchen Liu 1,  Rui Guo 2,  Chi Xue 3,  Xinwei Zhang 4,  Fanghao Xiao 4,  Xiangxuan Zhao 5,  Zhi Zhu 6,  Kai Li 7
Affiliations

Affiliations

  • 1 Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, Liaoning, 110001, China. Electronic address: liuyanchen0303@163.com.
  • 2 Department of Colorectal Surgery, Cancer Hospital of China Medical University, Cancer Hospital of Dalian University of Technology, Liaoning Cancer Hospital & Institute, No.44 Xiaobeyan Road, Dadong District, Shenyang, 110042, Liaoning Province, China.
  • 3 Department of Surgical Oncology and General Surgery, Key Laboratory of Precision Diagnosis and Treatment of Gastrointestinal Tumors, Ministry of Education, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, 110001, China.
  • 4 Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, Liaoning, 110001, China.
  • 5 Department of Innovative Engineering Technology in Traditional Chinese Medicine, Liaoning University of Traditional Chinese Medicine, No.79 Chongshandong Road, Shenyang, Liaoning, 110847, China. Electronic address: cmu_likai@163.com.
  • 6 Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, Liaoning, 110001, China. Electronic address: zhuzhi@cmu.edu.cn.
  • 7 Department of Surgical Oncology, The First Affiliated Hospital of China Medical University, 155 North Nanjing Street, Heping District, Shenyang, Liaoning, 110001, China. Electronic address: xiangxuanzhao@163.com.
PMID: 40983245 DOI: 10.1016/j.cbi.2025.111749
Abstract

Introduction: Traditional Chinese Medicine (TCM) has historically been employed in the treatment of various diseases, including malignancies such as Cancer. Phytosphingosine (PHS), a bioactive natural compound with antitumor properties, has attracted increasing attention in recent oncological studies.

Objectives: This study systematically investigates the pharmacological effects and molecular mechanisms of PHS in GC.

Methods: The small molecule targeting Secreted Frizzled-Related Protein 4 (SFRP4), identified through transcriptome Sequencing, was validated using Cellular Thermal Shift Assay (CETSA). To investigate the pharmacological effects of PHS, we employed Transwell invasion assays, colony formation assays, xenograft tumor models, and flow cytometry-based Apoptosis detection. Molecular mechanisms were explored via co-immunoprecipitation (Co-IP), immunohistochemistry (IHC), and Western blotting.

Result: The results demonstrate that PHS suppresses GC progression by dual mechanisms: (1) directly inducing Apoptosis via a dose-dependent increase in the Bax/Bcl-2 ratio and (2) more importantly, PHS achieves pivotal regulation of the Wnt signaling pathway through suppression of secreted SFRP4 phosphorylation, which promotes β-catenin ubiquitin-proteasomal degradation. Western blot and murine models confirmed reduced expression of Wnt signaling components (β-catenin, Cyclin D1, c-Myc) and significant tumor growth inhibition.

Conclusions: These findings reveal the SFRP4-Wnt axis as a central target for PHS, offering novel insights into its molecular action and highlighting its potential as a therapeutic strategy derived from traditional medicine, with clinical implications for targeting Wnt-driven gastric carcinogenesis.

Keywords

Gastric cancer; Phytosphingosine; SFRP4; Wnt pathway; β-catenin.

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