Tanshinone I as a novel ferritinophagy inducer triggers ferroptosis to suppress gastric cancer growth.

Authors

Baoyu Wei, Hailong Shen, Chengtao Sun, Guangzhao Pan, Qianqian Xu, Xiaoqing Guan, Jiangjiang Qin, Guoyin Kai

Published in

Phytomedicine : international journal of phytotherapy and phytopharmacology. Volume 160. Pages 158645. Jul 23, 2026. Epub Jul 23, 2026.

Abstract

Gastric cancer (GC) remains a major global health challenge, underscoring the urgent need for effective therapeutic strategies. Ferritinophagy-driven ferroptosis has recently emerged as a promising anticancer approach; however, potent pharmacological inducers and their modes of action remain largely unexplored.
This study aimed to investigate whether Tanshinone I (Tan I), a bioactive diterpenoid quinone, exerts antitumor effects against GC via ferritinophagy-dependent ferroptosis and to elucidate its underlying molecular mechanism.
Ferroptosis induction was evaluated using pharmacological rescue assays, flow cytometry, confocal microscopy, and transmission electron microscopy. Mechanistic investigations were conducted through quantitative proteomics, immunofluorescence staining, immunoblotting, and analyses of protein stability and ubiquitination. Target identification and validation were employed using limited proteolysis-mass spectrometry, cellular thermal shift assay, drug affinity responsive target stability, computational modeling, co-immunoprecipitation, and genetic manipulation. The antitumor efficacy of Tan I was further evaluated in orthotopic and patient-derived xenograft (PDX) models.
Tan I was identified as a potent inducer of ferroptosis and ferritinophagy in GC cells, as demonstrated by increased labile ferrous iron and lipid reactive oxygen species, characteristic mitochondrial abnormalities, and partial reversal of Tan I-induced cytotoxicity by ferroptosis inhibitors. Mechanistically, Tan I disrupted the interaction between the E3 ubiquitin ligase HUWE1 and the ferritinophagy cargo receptor NCOA4, thereby attenuating HUWE1-mediated ubiquitination and proteasomal degradation of NCOA4. Stabilization of NCOA4 enhanced ferritin turnover, resulting in iron overload, lipid peroxidation, mitochondrial dysfunction, and ultimately ferroptotic cell death. Notably, HUWE1 knockdown mimicked the key ferroptotic phenotypes induced by Tan I, whereas HUWE1 overexpression or NCOA4 knockdown mitigated these effects. Importantly, Tan I significantly suppressed tumor growth in both orthotopic and PDX models at well-tolerated doses while concomitantly activating ferritinophagy- and ferroptosis-associated markers in vivo.
By targeting the HUWE1-NCOA4 axis, Tan I induced ferritinophagy-dependent ferroptosis and exerted potent antitumor activity against GC, highlighting its potential as a lead compound for ferroptosis-based cancer therapies.

PMID:
42542057
Bibliographic data and abstract were imported from PubMed on 02 Aug 2026.

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