Fig. 3

The regulation of ferroptosis by JAK/STAT signaling pathways, focusing on the roles of different STAT proteins, including STAT1, STAT3, and STAT6, in modulating ferroptosis through pathways like SLC7A11 and GPX4 (Amino acid metabolism). STAT1 and ferroptosis: Upon activation by interferon-γ (IFN-γ), the JAK1/2-STAT1 pathway downregulates the cystine-glutamate antiporter (System Xc−), reducing cystine uptake and leading to GSH depletion. This suppression of the GSH/GPX4 axis results in increased lipid peroxidation and ferroptosis, contributing to cell death in diseases such as SS AMD. STAT3 and ferroptosis: The IL-6/JAK2/STAT3 pathway plays a crucial role in regulating ferroptos is resistance across various cancers, including RCC and HNSCC. IL-6 activates STAT3, promoting the transcription of SLC7A11, which enhances cystine uptake and GSH synthesis, thereby inhibiting ferroptosis. Additionally, the SHP-1/STAT3/SLC7A11 axis regulates the MCL1-BECN1 interaction, impacting ferroptosis in HCC and NSCLC. ARPC1A, transcriptionally regulated by STAT3, also inhibits ferroptosis in prostate cancer by reducing GPX4 and SLC7A11 expression, facilitating tumor progression. STAT6 and ferroptosis: In conditions such as asthma and ALI, IL-13 activates the JAK2/STAT6 pathway, which promotes the degradation of SLC7A11 via SOCS1, leading to increased ferroptosis in airway epithelial cells. Furthermore, STAT6 inhibits P53 acetylation, thereby enhancing SLC7A11 expression, which mitigates ferroptosis during lung injury