ORIGINAL RESEARCH article
Front. Oncol.
Sec. Gastrointestinal Cancers: Hepato Pancreatic Biliary Cancers
Volume 15 - 2025 | doi: 10.3389/fonc.2025.1531420
Metformin Inhibits the Proliferation of Hepatocellular Carcinoma Cells through Inducing Ferroptosis Analyzed by Phosphoproteomics
Provisionally accepted
- 1Affiliated Hospital, Ningbo University, Ningbo, Zhejiang Province, China
- 2University of Franche-Comté, Besançon, Franche-Comté, France
- 3Ningbo University, Ningbo, Zhejiang Province, China
- 4Department of Health Science Center, Ningbo University, Ningbo, Zhejiang, China
- 5Université Clermont Auvergne, Clermont-Ferrand, Auvergne, France
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This study aims to investigate the effects of Metformin on hepatocellular carcinoma cell lines, cell lines and explores the molecular mechanisms underlying. Bel-7402 and HepG2 cells were treated with varying concentrations of Metformin and ferrostatin-1 to assess cytotoxicity using the MTT assay. Protein expression and phosphorylation changes were analyzed through a phosphoproteomics approach and further bioinformatics analysis, including Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. The data from phosphoproteomics were confirmed by western blot. Metformin treatment significantly reduced cell viability in a concentration-and time-dependent manner. Phosphoproteomics analysis identified differentially expressed proteins (DEPs) primarily associated with ferroptosis and cellular metabolism. Further GO and KEGG analyses revealed the involvement of DEPs in nucleotide biosynthesis, membrane transport, and metabolic pathways. Then the bioinformatic data were verified through MTT and western blot, the results showed that ferrostatin-1 could partly reverse the inhibitory effects of Metformin, suggesting the involvement of ferroptosis. Moreover, the modulation of autophagy and ferroptosis-related proteins by Metformin was confirmed by western blot. Our findings demonstrate that Metformin induces ferroptosis in Bel-7402 and HepG2 cell lines, potentially offering a novel therapeutic strategy for the treatment of hepatocellular carcinoma. The phosphoproteomics analysis provides insights into the molecular mechanisms by which Metformin exerts its anti-cancer effects.
Keywords: Metformin, Hepatocellular Carcinoma, ferroptosis, phosphoproteomics, Cell viability
Received: 20 Nov 2024; Accepted: 13 May 2025.
Copyright: © 2025 Sun, Yu, Shan, Dai, Gaucherot, LU and Mao. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence: Caide LU, Ningbo University, Ningbo, 315211, Zhejiang Province, China
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