Fig. 4

The regulation of ferroptosis through the interaction of iron metabolism and the STAT3/NRF2 pathway. In conditions like osteosarcoma and periodontitis, STAT3 activates NRF2, promoting antioxidant defense and osteogenic differentiation by upregulating key genes such as GPX4 and SLC7A11, which protect against ferroptosis. IL-6/STAT3 signaling increases hepcidin expression, inhibiting ferroportin and leading to iron accumulation and ferroptosis through the Fenton reaction. Additionally, STAT3 drives ferritin degradation via NCOA4, releasing iron and exacerbating ferroptosis in cardiac injury. In chemotherapy-resistant osteosarcoma, the STAT3/NRF2/GPX4 axis enhances resistance to ferroptosis, while targeting this pathway could sensitize cancer cells to ferroptosis inducers. The STAT3/HO-1 pathway in liver injury also contributes to ferroptosis by promoting iron dysregulation and oxidative stress. This integration highlights STAT3’s pivotal role in modulating ferroptosis through iron metabolism and antioxidant pathways across different diseases