Gigantol induces ferroptosis in gastric cancer via methyltransferase-like 3/YTH domain-containing family protein 2-mediated β-catenin degradation.

Authors

Chen Wang, Didi Zhao, Haoqi Jiang, Ningning Zhang, Yuqing Wang, Jing Ni, Qihong Zhao, Anla Hu

Published in

Phytomedicine : international journal of phytotherapy and phytopharmacology. Volume 159. Pages 158529. Jun 29, 2026. Epub Jun 29, 2026.

Abstract

Gastric cancer (GC) poses a significant therapeutic challenge worldwide, highlighting an urgent need for novel and effective treatment strategies. Recently, natural compounds targeting ferroptosis have emerged as promising candidates in the management of GC. Gigantol is a natural bibenzyl compound extracted from the Dendrobium genus, a traditional Chinese medicinal plant used for centuries to treat various gastric disorders. However, the anti-tumor effects of gigantol on GC and the underlying mechanisms remain largely unexplored.
This study aimed to investigate the anti-tumor effects of gigantol on GC, elucidate the underlying mechanisms, and explore its combined effects with apatinib.
CCK-8, colony formation, transwell, DCFH-DA staining, and ELISA assays were performed to evaluate the anti-tumor effects of gigantol on GC in vitro. Mechanistic explorations were conducted via MeRIP-qPCR, RIP-qPCR, Western blot, cell transfection, and RNA stability assays. Cell-derived xenograft and tail vein-lung metastatic models were utilized to evaluate the efficacy of gigantol in vivo.
Gigantol significantly inhibited the proliferation and metastasis of GC cells, which may be associated with the induction of ferroptosis. Mechanistically, gigantol increased m⁶A levels on β-catenin mRNA by promoting METTL3. Then, YTHDF2 was recruited to facilitate the degradation of β-catenin mRNA. The consequent depletion of β-catenin led to the downregulation of GPX4, which in turn triggered ferroptosis, ultimately inhibiting GC progression. Furthermore, the combination of gigantol and apatinib potentiated anti-tumor efficacy, likely through enhanced induction of ferroptosis.
This study suggests that gigantol exerts anti-tumor effects on GC, at least in part, by inducing ferroptosis via the METTL3/m⁶A/β-catenin/GPX4 pathway, providing a potential therapeutic strategy for GC patients.

PMID:
42391814
Bibliographic data and abstract were imported from PubMed on 03 Jul 2026.

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