Targeting critical pathways in ferroptosis and enhancing antitumor therapy of platinum drugs for colorectal cancer - review

Sep 24, 2026

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Colorectal cancer (CRC) often shows resistance to platinum drugs, and suppression of ferroptosis is implicated in this resistance, though the mechanism still requires clarification. This review aggregates evidence on oxaliplatin resistance and examines how ferroptosis may regulate oxaliplatin effects. It discusses iron homeostasis, oxidative stress, and lipid peroxidation in CRC ferroptosis initiation, highlighting c-Myc/NRF2 and NRF2/GPX4 signaling. It further summarizes ferroptosis inducers, GPX4 inhibitors, and natural products for reversing resistance and considers relevant molecular targets, challenges, and future opportunities for CRC therapy.

LanguageEnglish

CategoryHealthcare

FormatPDF

Pages30

Reading Time1 h 16 min

AccessFree to download

Abstract

Introduction

Colorectal cancer and oxaliplatin resistance

Ferroptosis as a regulatory cell death mechanism

Key molecular findings in ferroptosis research

Review SCIENCE PROGRESS Targeting critical pathways inferroptosis and enhancing antitumor therapy of Platinum drugs for colorectal cancer Science Progress 2023, Vol. 106(1) 1–30 © The Author(s) 2023 Article reuse guidelines: [sagepub.com/journals-permissions](sagepub.com/journals-permissions)[ ](sagepub.com/journals-permissions)[DOI: 10.1177/00368504221147173](DOI: 10.1177/00368504221147173)[ ](DOI: 10.1177/00368504221147173)[journals.sagepub.com/home/sci](journals.sagepub.com/home/sci) Gang Wang 1 , Jun-Jie Wang 1, Zhu Zhi-Min 1, Xiao-Na Xu2, Feng Shi2 and Xing-Li Fu2 1 Department of Pharmaceutics, Shanghai Eighth People’s Hospital, Jiangsu University, Shanghai, China 2Department of Medicine, Jiangsu University, Zhenjiang City, Jiangsu Province, China Abstract Colorectal cancer (CRC) can be resistant to platinum drugs, possibly through ferroptosis suppression, albeit the need for further work to completely understand this mechanism. This work aimed to sum up current ﬁndings pertaining to oxaliplatin resistance (OR) or resistance to ascertain the potential of ferroptosis to regulate oxaliplatin effects. In this review, tumor development relating to iron homeostasis, which includes levels of iron that ascertain cells’ sensitivity to ferroptosis, oxidative stress, or lipid peroxidation in colorectal tumor cells that are connected with ferroptosis initiation, especially the role of c-Myc/NRF2 signaling in regulating iron homeostasis, coupled with NRF2/GPX4-mediated ferroptosis are discussed. Importantly, ferroptosis plays a key role in OR and ferroptotic induction may substantially reverse OR in CRC cells, which in turn could inhibit the imbalance of intracellular redox induced by oxaliplatin and ferroptosis, as well as cause chemotherapeutic resistance in CRC. Furthermore, fundamental research of small molecules, ferroptosis inducers, GPX4 inhibitors, or natural products for OR coupled with their clinical applications in CRC have also been summarized. Also, potential molecular targets and mechanisms of small molecules or drugs are discussed as well. Suggestively, OR of CRC cells could signiﬁcantly be reversed by ferroptosis induction, wherein this result is discussed in the current review. Prospectively, the existing literature discussed in this review will provide a solid foundation for scientists to research the potential use of combined anticancer drugs which can overcome OR via targeting various mechanisms of ferroptosis. Especially, promising therapeutic strategies, challenges ,and opportunities for CRC therapy will be discussed. Corresponding author: Gang Wang, Department of Pharmaceutics, Shanghai Eighth People’s Hospital, Jiangsu University, Shanghai 200235, China. [Email:wangan139@163.com](Email:wangan139@163.com) Creative Commons Non Commercial CC BY-NC: This article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License ([https://creativecommons.org/licenses/by-nc/4.0/](https://creativecommons.org/licenses/by-nc/4.0/)) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as speciﬁed on the SAGE and Open Access page ([https://us.sagepub.com/en-us/nam/open-access-at-sage](https://us.sagepub.com/en-us/nam/open-access-at-sage)). Keywords Colorectal cancer, ferroptosis, drug resistance, Platinum drugs, NRF2/GPX4, iron homeostasis Introduction Colorectal cancer (CRC) is diagnosed routinely with distant metastases at a higher rate, thereby making it one of the most predominant tumors in the world.1 A usual phenomenon associated with treatment failure of colorectal tumors following surgery is oxaliplatin resistance (OR).2 Accordingly, the unmet need to reverse OR coupled with approaches to improve the effectiveness of anticancer drugs on CRC in a long-acting fashion, as well as prolonging patients’ lives has attracted much attention from scientists and clinicians. A

FAQs

How is oxaliplatin resistance in colorectal cancer linked to ferroptosis?

Oxaliplatin resistance may be driven by ferroptosis suppression. The review explains that restoring ferroptosis induction could reverse this resistance in CRC cells.

Which signaling pathways are emphasized in regulating iron homeostasis and ferroptosis?

The review focuses on c-Myc/NRF2 in controlling iron homeostasis and NRF2/GPX4-mediated ferroptosis as key regulatory routes.

What types of agents are summarized for overcoming platinum-drug resistance?

The review summarizes small molecules and ferroptosis inducers, GPX4 inhibitors, and natural products, along with their potential clinical applications in CRC.

Sep 24, 2026

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