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

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.