The Dual Roles of STAT3 in Ferroptosis: Mechanism, Regulation and Therapeutic Potential

Jinghui Xie,* Dan Luo,* Pengfei Xing, Weijun Ding School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weijun Ding, Email [email protected]: Ferroptosis, an iron-dependent programmed mechanism of cell death that is driven by lipid peroxidation, is an important pathogenic factor in oncological and non-oncological disorders. Dysregulation of iron and lipid metabolism profoundly influences disease progression through ferroptosis modulation. Signal transducer and activator of transcription 3 (STAT3), a transcriptional regulator, regulates ferroptosis by binding to promoters of key molecules such as solute carrier family 7 member 11 (SLC7A11), glutathione peroxidase 4 (GPX4), and ferritin heavy chain 1 (FTH1). In this review, we described the role of STAT3 in supporting tumors survival by suppressing ferroptosis in malignancies, and bidirectionally regulating ferroptosis in non-tumors to regulate the development of the disease. We also reported emerging therapeutic strategies that target STAT3-mediated ferroptosis, including natural phytochemicals, inhibitors, and nanotechnology-enabled drug delivery systems. These advancements deepen the mechanistic understanding of ferroptosis regulation, and provide new theoretical bases and strategies to treat ferroptosis-related diseases.Keywords: STAT3, dual roles, ferroptosis, cancer, vector therapy