Emerging Role of Ferroptosis in Chemotherapy-Associated Hepatorenal Toxicity: Mechanistic Insights and Toxicological Perspectives

Abstract

Chemotherapy-induced hepatorenal toxicity is one of the most predominant dose-limiting obstacles in oncological pharmacotherapy, and the molecular mechanisms surrounding its pathogenesis are still poorly defined. Lipid peroxide toxicity-induced, iron-dependent, nonapoptotic types of regulated cell death called ferroptosis have emerged as a mechanically important process in the organ injury caused by chemotherapy. In this Keynote Review, we will summarize recent evidence showing the implication of ferroptosis in liver and kidney toxicity of platinum-based drugs, anthracycline drugs, tyrosine kinase inhibitors, and some targeted drugs. We identify key mechanisms underlying ferroptosis, including abnormalities of the axis of system Xc^–/glutathione peroxidase4 (GPX4) axis, changes in iron homeostasis, and activation of ferritinophagy and the maladaptive effects of polyunsaturated fatty acid oxidation. The role of the hepatorenal microenvironment is discussed in detail, with a particular focus on mitochondrion-related abnormalities, interaction between endocrine and immune cells, and mitochondrion-endoplasmic reticulum-stress coupling, as well as interactions with ferroptosis suppressor protein 1 (FSP1)/CoQ10 and dihydroorotate dehydrogenase (DHODH) pathways. Data from the preclinical models are combined with new treatment data to develop a linear toxicological story. The utility of the use of biomarker strategies such as plasma malondialdehyde, 4-hydroxynonenal adducts, circulating GPX4, and urinary prostaglandin-like isoprostanes in diagnosis and monitoring is examined. The role of therapeutic interventions such as Nrf2 activators, liproxstatin1, ferrostatin1, and iron chelators for reducing organ-specific ferroptotic injury without reducing effectiveness as antineoplastic is briefly explored. This Review highlights ferroptosis as a therapeutic target that is amenable to therapy and suggests a systematic approach for its integration into toxicological risk classifications during drug development for cancer treatment.