Ferroptosis: A prospective therapeutic target for radiotherapy- and chemotherapy-induced gastrointestinal inflammation

Ferroptosis is a unique mode of cell death driven by iron-dependent lipid peroxidation, and the process is regulated by a variety of cellular metabolic pathways, including redox homeostasis, iron processing, and lipid metabolism. It has been shown that radiotherapy- and chemotherapy-induced gastrointestinal (GI) inflammation exhibits the key features of ferroptosis, including iron deposition, glutathione (GSH) depletion, glutathione peroxidase 4 (GPX4) inactivation and lipid peroxidation. In this paper, we found that ferroptosis plays an important role in radiotherapy- and chemotherapy-induced GI inflammation, and that elevating GSH levels, activating GPX4, inhibiting elevated levels of lipid peroxidation, and maintaining iron homeostasis significantly alleviated radiotherapy- and chemotherapy-induced GI inflammation. This suggests that ferroptosis may be a new target for the treatment of GI inflammation. In addition, we systematically summarize the potential mechanisms of traditional Chinese medicine (TCM) and its active ingredients in the treatment of GI inflammation, which may be effective in ameliorating radiotherapy- and chemotherapy-induced GI by acting on the key signaling pathways and mediators, such as Nrf2/HO-1, GSH/GPX4, polyunsaturated fatty acids (PUFAs), iron, and organic peroxides, which in turn inhibit the process of ferroptosis, and thereby effectively ameliorate the radiotherapy- and chemotherapy-induced GI inflammation. This finding provides a new potential approach for the treatment of such GI inflammation and demonstrates the potential value of TCM in modern medical treatment.