Ferroptosis in Cancer Therapy: Mechanisms, Small Molecule Inducers, and Novel Approaches

Abstract

Ferroptosis, a unique form of programmed cell death, is initiated by an excess of iron accumulation and lipid peroxidation-induced damage. There is a growing body of evidence indicating that ferroptosis plays a critical role in the advancement of tumors. The increased metabolic activity and higher iron levels in tumor cells make them particularly vulnerable to ferroptosis. As a result, the targeted induction of ferroptosis is becoming an increasingly promising approach for cancer treatment. This review offers an overview of the regulatory mechanisms of ferroptosis, delves into the mechanism of action of traditional small molecule ferroptosis inducers and their effects on various tumors. In addition, the latest progress in inducing ferroptosis using new means such as proteolysis-targeting chimeras (PROTACs), photodynamic therapy (PDT), sonodynamic therapy (SDT) and nanomaterials is summarized. Finally, this review discusses the challenges and opportunities in the development of ferroptosis-inducing agents, focusing on discovering new targets, improving selectivity, and reducing toxic and side effects.

Keywords:

• ferroptosis inducers
• small molecules
• PROTACs
• PDT
• SDT
• nanomaterials

Summary

Ferroptosis is an iron-dependent mode of programmed cell death. Ferroptosis has become a hot research topic since it was proposed in 2012. With in-depth research on the mechanism of ferroptosis and its targets, various ferroptosis inducers have been discovered and developed. At the same time, research on its application in cancer prevention and treatment has also deepened. Under the predicament that tumors are resistant to traditional therapies such as chemotherapy and radiotherapy and have poor therapeutic effects, the proposal and development of ferroptosis-inducing therapies have provided new ideas and prospects for tumor treatment.

In this article, we introduce the mechanism of ferroptosis, the various types of ferroptosis inducers, and the application of ferroptosis-inducing therapies in the field of PDT and SDT. The comprehensive and systematic summary of small molecule drug classes of ferroptosis inducers provides ideas for designing and optimizing a new generation of small molecule drugs. The summary of the research progress of ferroptosis inducers in PROTACs, nanomaterials, PDT, and SDT provides a reference for the development and clinical translation of ferroptosis inducers in new fields. We also compare the advantages and disadvantages of various ferroptosis inducers. More importantly, we present the challenges and opportunities for developing ferroptosis inducers. We not only show the problems encountered in developing ferroptosis inducers but also propose solutions to solve the problems. In conclusion, we hope that the comprehensive summary and in-depth discussion of ferroptosis inducers will provide a direction for further research and development and clinical translation of ferroptosis inducers, thus bringing more effective treatment for tumor patients.

Acknowledgment

YiLin Luo, XinYue Bai and Lei Zhang share first authorship.

Author Contributions

YL.L, XY.B, L.Z is responsible for conceptualizing, designing, and writing the content of the article. QQ.H, N.Z, JZ.C, MZ.H is responsible for literature research, interpretation, and data collection. X.L.L is responsible for conceptualizing, funding, and guiding this article. All authors have critically reviewed the knowledge content of the final version of the article and approved the submitted version.

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agree to be accountable for all aspects of the work.

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This review was supported by the grants from Natural Science Foundation of Shaanxi Province (2023-JC-QN-0125 to L.X.L.), and Yan’ an science and technology bureau (2023-SFGG-141 to L.X.L.).