A new wave of scientific understanding is placing ferroptosis, a distinct form of iron-dependent cell death, at the forefront of efforts to overcome drug resistance in digestive cancers. These cancers, which include gastric, colorectal, liver, pancreatic, and esophageal malignancies, remain among the most challenging to treat due to their ability to evade standard therapies.
A central issue in cancer care is the persistence of chemotherapy resistance, where tumor cells adapt and survive despite treatment. Ferroptosis offers a fundamentally different approach by exploiting the unique metabolic vulnerabilities of cancer cells. Rather than relying on traditional pathways like apoptosis, ferroptosis drives cell death through the accumulation of toxic lipid molecules and oxidative damage, creating a new opportunity to target resistant tumors.
At the heart of this process are three key mechanisms: iron metabolism, lipid peroxidation, and the GPX4-regulated pathway. These systems interact to generate lethal oxidative stress within cancer cells. When properly activated, they can overwhelm the defenses that tumors use to survive, leading to controlled cell death even in cases where other treatments have failed.
The complexity of tumor biology plays a significant role in resistance. Factors such as tumor heterogeneity, metabolic alterations, and the tumor microenvironment contribute to the ability of cancer cells to withstand therapy. Interactions between cancer cells and surrounding tissues, including immune and stromal cells, create protective conditions that limit the effectiveness of conventional treatments. These same factors, however, also influence how susceptible tumors are to ferroptosis-based strategies.
Emerging insights show that targeting ferroptosis could help reverse resistance across multiple cancer types. In particularly aggressive diseases such as pancreatic ductal adenocarcinoma and hepatocellular carcinoma, activating ferroptosis pathways may restore responsiveness to treatment. Similar potential is being observed in colorectal and gastric cancers, where disrupting the molecular defenses against ferroptosis can weaken tumor survival mechanisms.
Another promising direction involves combining ferroptosis-based approaches with existing treatments. Integrating these strategies with targeted therapies or immunotherapy could enhance overall effectiveness and reduce the likelihood of relapse by attacking cancer through multiple pathways simultaneously.
As the understanding of ferroptosis continues to evolve, it is becoming a powerful concept in the future of cancer treatment. By directly addressing the challenge of treatment resistance, this approach opens the door to more effective and lasting therapies for patients facing some of the most difficult forms of digestive cancer.
# # # # # #
Genes & Diseases publishes rigorously peer-reviewed and high quality original articles and authoritative reviews that focus on the molecular bases of human diseases. Emphasis is placed on hypothesis-driven, mechanistic studies relevant to pathogenesis and/or experimental therapeutics of human diseases. The journal has worldwide authorship, and a broad scope in basic and translational biomedical research of molecular biology, molecular genetics, and cell biology, including but not limited to cell proliferation and apoptosis, signal transduction, stem cell biology, developmental biology, gene regulation and epigenetics, cancer biology, immunity and infection, neuroscience, disease-specific animal models, gene and cell-based therapies, and regenerative medicine.
Scopus CiteScore: 8.4 |Impact Factor: 9.4
# # # # # #
More information: https://www.keaipublishing.com/en/journals/genes-and-diseases/
Editorial Board: https://www.keaipublishing.com/en/journals/genes-and-diseases/editorial-board/
All issues and articles in press are available online in ScienceDirect (https://www.sciencedirect.com/journal/genes-and-diseases).
Submissions to Genes & Diseases may be made using Editorial Manager (https://www.editorialmanager.com/gendis/default.aspx).
Print ISSN: 2352-4820
eISSN: 2352-3042
CN: 50-1221/R
Contact Us: editor@genesndiseases.cn
X (formerly twitter): @GenesNDiseases (https://x.com/GenesNDiseases)
# # # # # #
Reference
Wenjie Chen, Liang Han, Jizhou Wang, Linjiang Song, Ferroptosis: The dawn of reversing drug resistance in digestive cancers, Genes & Diseases, Volume 13, Issue 2, 2026, 101873, https://doi.org/10.1016/j.gendis.2025.101873

Funding
National Natural Science Foundation of China 82305011