Ferrocene conjugated glutathione consumption for enhanced ferroptosis therapy and chemotherapy

A new study led by investigators from Professor Jiandu Lei of Beijing Forestry University had found that the "multi-machine integrated" combined strategy of chemotherapy and ferroptosis could enhance antitumor effects and had good biosafety.

Chemotherapy, as a mainstay of colorectal cancer treatment, is prone to tumor resistance and side effects due to its apoptotic pathways. Ferroptosis, as an effective form of non-apoptotic cell death, can overcome chemotherapy apoptosis-induced resistance. One of the reasons for its emergence as a potential target for cancer therapy is its potency in removing drug-resistant tumour cells and highly metastatic tumour cells undergoing epithelial-mesenchymal transition. Whereas, recurrence and metastasis remain the leading causes of tumour-related deaths in colorectal cancer patients. Therefore, the combination of apoptosis and ferroptosis is expected to be an effective strategy for the treatment of colorectal cancer. However, high glutathione and insufficient intracellular iron content in the tumor environment limit the efficiency of ferroptosis-mediated anticancer. Not only that, simultaneous intracellular delivery of iron sources, ferroptosis inducers, and chemotherapeutic agents remains a major challenge.

A team led by Professor Jiandu Lei from Beijing Forestry University had recently developed a self-assembled co-delivery nano-prodrug (PFSH@HCPT). The branched chains were covalently conjugated with ferrocene (Fc) and disulfide bonds-modified honokiol, and the system was loaded with 10-hydroxycamptothecin (HCPT) to form nanomicelles. In the tumor microenvironment, high levels of GSH triggered disulfide bonding and induced disassembly of PFSH@HCPT, releasing HCPT, HNK, and Fc. As a chemotherapeutic agent, HCPT not only induced tumor cell apoptosis but also provided H₂O₂ for the Fenton reaction mediated by Fc, thereby enhancing ferroptosis. Fc triggered the Fenton reaction, inducing ferroptosis. HNK inhibited GPX4 activity to enhance ferroptosis on the one hand, and further induced cell death via apoptosis on the other hand. Meanwhile, the combined strategy of HNK-mediated resistance and ferroptosis induced resistance mechanism further overcame the resistance of HCPT and significantly improved the therapeutic efficacy. This nano system achieved the efficacy of “multi-machine integrated” and may provide new insights into more effective anti-colon cancer treatments.

The team published their study in Nano Research with the DOI of 10.26599/NR.2025.94907298.

"In this study, we combined a 'multi-machine integrated' therapeutic strategy, which not only enhanced the efficacy of chemotherapy and ferroptosis through dual mechanisms but also reduced chemotherapy-induced tumor resistance through dual mechanisms. The research team expects this study spur development of nano-prodrug systems to improve therapeutic outcomes and provide support for clinical drug research." said Jiandu Lei, corresponding author of the paper, professor in the School of Materials Science and Technology.

This work was supported by the Fundamental Research Funds for the Central Universities (PTYX202449).

About the Authors

Dr. Jiandu Lei is a distinguished professor of MOE Engineering Research Center of Forestry Biomass Materials and Bioenergy, Beijing Forestry University, China. His research interests focus on the design, construction and application of biomaterials and the new separation and analysis media. Until now, he has published more than 70 papers in Advanced Functional Materials and other journals, presided lots of national/provincial scientific research projects, owns more than 50 invention patents.

About Nano Research

Nano Research is a peer-reviewed, open access, international and interdisciplinary research journal, sponsored by Tsinghua University and the Chinese Chemical Society, published by Tsinghua University Press on the platform SciOpen. It publishes original high-quality research and significant review articles on all aspects of nanoscience and nanotechnology, ranging from basic aspects of the science of nanoscale materials to practical applications of such materials. After 17 years of development, it has become one of the most influential academic journals in the nano field. Nano Research has published more than 1,000 papers every year from 2022, with its cumulative count surpassing 7,000 articles. In 2023 InCites Journal Citation Reports, its 2023 IF is 9.6 (9.0, 5 years), and it continues to be the Q1 area among the four subject classifications. Nano Research Award, established by Nano Research together with TUP and Springer Nature in 2013, and Nano Research Young Innovators (NR45) Awards, established by Nano Research in 2018, have become international academic awards with global influence.