Identification of a Novel Ferroptosis Inducer for Gastric Cancer Treatment Using Drug Repurposing Strategy
Related Experiment Video
Updated: Sep 4, 2025
Author Spotlight: Genetic Profiling for Fluorouracil Response in Gastric Cancer
Published on: May 10, 2024
Jinping Zhang1, Meimei Gao2, Ying Niu1
1Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.
Abstract:
Gastric cancer remains one of the major contributors to global cancer mortality, although there is no promising target drug in clinics. Hence, the identification of novel targeted drugs for gastric cancer is urgent. As a promising strategy for inducing ferroptosis for gastric cancer treatment, the ferroptosis inducer is a potential drug. Nevertheless, no ferroptosis inducer has entered clinics. So, our purpose was to identify a novel ferroptosis inducer for gastric cancer treatment using a drug repurposing strategy. Firstly, using a drug repurposing strategy with the aid of a commercialized compound library, HC-056456, a small molecule bioactive CatSper channel blocker, was characterized to inhibit the growth of gastric cancer line MGC-803. At the same time, this anti-proliferation effect can be blocked by ferrostatin-1, a ferroptosis inhibitor, indicating that HC-056456 is a ferroptosis inducer. Then, HC-056456 was identified to decrease GSH content via p53/SLC7A11 signaling pathway. Then Fe2+ and lipid peroxide were accumulated when cells were exposed to HC-056456. Finally, HC-056456 was found to suppress the growth of gastric cancer cells by increasing p53 and repressing SLC7A11 in vivo but not in the presence of ferrostatin-1. In sum, we systematically elucidate that HC-056456 exerts anti-gastric cancer effect by provoking ferroptosis in vitro and in vivo, suggesting its potential role in gastric cancer treatment.
Insights
A novel ferroptosis inducer, HC-056456, effectively suppresses gastric cancer growth by targeting the p53/SLC7A11 pathway. This drug repurposing strategy shows promise for developing new gastric cancer treatments.
Area of Science:
- Oncology
- Biochemistry
- Drug Discovery
Background:
- Gastric cancer is a leading cause of cancer mortality globally, with limited targeted therapies.
- Developing novel drugs, particularly ferroptosis inducers, is crucial for effective gastric cancer treatment.
- No ferroptosis inducers have yet reached clinical application.
Purpose of the Study:
- To identify a novel ferroptosis inducer for gastric cancer treatment using drug repurposing.
- To investigate the mechanism of action of the identified compound in gastric cancer cells.
- To evaluate the efficacy of the compound both in vitro and in vivo.
Main Methods:
- Drug repurposing using a commercialized compound library to screen for gastric cancer inhibitors.
- Characterization of HC-056456's anti-proliferative effects and confirmation of ferroptosis induction using ferrostatin-1.
- Analysis of the p53/SLC7A11 signaling pathway, GSH levels, Fe2+, and lipid peroxide accumulation.
- In vitro and in vivo studies to assess tumor growth suppression.
Main Results:
- HC-056456, a CatSper channel blocker, was identified as a potent inhibitor of gastric cancer cell growth (MGC-803).
- HC-056456 induces ferroptosis by decreasing GSH, increasing Fe2+ and lipid peroxide accumulation via the p53/SLC7A11 pathway.
- The compound suppressed gastric cancer growth in vivo by modulating p53 and SLC7A11, an effect blocked by ferrostatin-1.
Conclusions:
- HC-056456 effectively exerts anti-gastric cancer effects by inducing ferroptosis both in vitro and in vivo.
- This study highlights HC-056456 as a potential therapeutic agent for gastric cancer treatment.
- The findings suggest a promising role for drug repurposing in identifying novel ferroptosis inducers for cancer therapy.
