Ferroptosis - The dawn of reversing drug resistance in digestive cancers

Sep 23, 2026

Ferroptosis, an iron-dependent regulated cell death marked by lipid peroxidation, is highlighted as a promising approach to overcome resistance to chemotherapy in digestive system cancers. The review details the molecular basis of ferroptosis, emphasizing the GPX4-regulated pathway, iron metabolism, and lipid peroxidation, and connects these drivers to mechanisms underlying drug resistance. It further discusses tumor heterogeneity, tumor–stroma interactions, apoptosis abnormalities, metabolic changes, and the tumor microenvironment, and summarizes disease-specific ferroptosis resistance and strategies to induce ferroptosis. Future work should translate these mechanisms into clinical targeted and combination therapies to improve outcomes.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages18

Reading Time45 min

AccessFree to download

Introduction

Mechanisms of ferroptosis

Ferroptosis resistance in digestive cancers

Esophageal squamous cell carcinoma

Gastric cancer

Hepatocellular carcinoma

Pancreatic ductal adenocarcinoma

Colorectal cancer

Strategies to induce ferroptosis and reverse drug resistance

Future perspectives

Genes & Diseases (2026) 13, 101873 Available online [at](at www.sciencedirect.com)[ www.sciencedirect.com](at www.sciencedirect.com) ScienceDirect journal [homepage:](homepage: www . keaipublishing. com/en/journals/genes-diseases)[ www . keaipublishing. com/en/journals/genes-diseases](homepage: www . keaipublishing. com/en/journals/genes-diseases) REVIEW ARTICLE Ferroptosis: The dawn of reversing drug resistance in digestive cancers Wenjie Chen a, Liang Han b, Jizhou Wang a, Linjiang Song a,* a School of Medical and Life Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 611137, China b Hospital of Chengdu University of Traditional Chinese Medicine, School of Clinical Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan 610075, China Received 23 March 2025; received in revised form 7 July 2025; accepted 5 September 2025 Available online 26 September 2025 KEYWORDS Chemotherapy; Digestive cancers; Drug resistance; Ferroptosis; Targeted therapy Abstract Ferroptosis, a form of iron-dependent cell death characterized by lipid peroxidation, has emerged as a promising strategy to overcome resistance to chemotherapy. This review explores the mechanisms of ferroptosis and its potential to reverse drug resistance in digestive system cancers. We summarize recent advances in understanding the GPX4-regulated pathway, iron metabolism, and lipid peroxidation as key drivers of ferroptosis. It also highlights the roles of tumor heterogeneity, tumor—stroma interactions, abnormal apoptosis, metabolic alterations, and the tumor microenvironment in drug resistance. Specific mechanisms of ferroptosis resistance in esophageal squamous cell carcinoma, gastric cancer, hepatocellular carcinoma, pancreatic ductal adenocarcinoma, and colorectal cancer are discussed, along with strategies to induce ferroptosis to reverse drug resistance. Future research should focus on translating these findings into clinical applications through targeted therapies and combination treatments to improve patient outcomes. © 2025 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. , Ltd. This is an open access article under the CC BY license ([http://creativecommons.org/](http://creativecommons.org/)[ ](http://creativecommons.org/)[licenses/by/4.0/](licenses/by/4.0/) ) . Introduction * Corresponding author. E-mail address: [songlinjiang@cdutcm.edu.cn](songlinjiang@cdutcm.edu.cn) (L. Song). Peer review under the responsibility of Chongqing Medical University. Cancers of the digestive system include esophageal squamous cell carcinoma, gastric cancer, colorectal cancer, hepatocellular carcinoma, pancreatic cancer, and others that develop in the digestive tract from the mouth to the anus and related organs.1 Cancers of the digestive system account for one-quarter of malignancies recorded globally and more than one-third of all cancer-related fatalities.2 [https://doi.org/10.1016/j.gendis.2025.101873](https://doi.org/10.1016/j.gendis.2025.101873) 2352-3042/© 2025 The Authors. Publishing services by Elsevier B.V. on behalf of KeAi Communications Co. , Ltd. This is an open access article under the CC BY license ([http://creativecommons.org/licenses/by/4.0/](http://creativecommons.org/licenses/by/4.0/)). Digestive system cancers are among the most prevalent malignancies, which pose a significant threat to human health.3 At the same time, current diagnostic and treatment technologies have limitations, including low patient cure rates and severe side effects. Although chemotherapy is widely used to treat cancers, one key factor contributing to chemotherapy failure is cancer cell resistance to anticancer drugs.4 As a result, it is crucial to develop innovative approaches to treating cancers of the digestive system. Drug resistance is often described as the lower sensitivity orineffectiveness of a pathogen or cancer cells to a drug after multiple exposures

FAQs

What is ferroptosis and why is it relevant to drug resistance in digestive cancers?

Ferroptosis is an iron-dependent regulated cell death characterized by lipid peroxidation. The review explains that ferroptosis can counter chemotherapy resistance, and that resistance to ferroptosis can function as a clinically relevant mechanism of tumor drug resistance.

Which pathways and biological processes drive ferroptosis according to the review?

The review emphasizes the GPX4-regulated pathway, abnormal iron metabolism, and lipid peroxidation. It also links ferroptosis to iron, lipid, and amino acid metabolism and to the balance of ferroptosis inducers and inhibitors.

How does the tumor microenvironment and tumor biology contribute to drug resistance?

It discusses roles for tumor heterogeneity, tumor–stroma interactions, abnormal apoptosis, metabolic alterations, and the tumor microenvironment in shaping drug resistance, and relates these factors to mechanisms of ferroptosis and its resistance.

Sep 23, 2026

Uploaded by RuangKosong