The role of STAT3 in regulating ferroptosis in cancer: molecular mechanisms and targeted therapeutic perspectives.

Cancer is still a big health problem and a growing issue worldwide. Colorectal cancer (CRC), as a highly prevalent malignancy worldwide, faces critical challenges in overcoming therapy resistance and recurrence. Beyond classical cell death pathways like apoptosis, targeting alternative forms of programmed cell death (PCD) may provide novel strategies to circumvent current therapeutic limitations. Ferroptosis-an iron-dependent, lipid peroxidation-driven form of PCD-exerts dual roles in tumor modulation, with the STAT3 signaling pathway identified as its central regulatory hub. This review systematically elucidates the molecular mechanisms by which STAT3 suppresses ferroptosis in tumor cells through regulating glutathione peroxidase 4 (GPX4), iron metabolism genes (like TFR1, FTH1), and oxidative stress pathways. Furthermore, it explores how natural products (like baicalein, ginsenoside Rh3) and synthetic inhibitors (like W1131) targeting STAT3 inhibition modulate this signaling axis to induce ferroptosis across diverse tumor cell types. Nevertheless, off-target effects, drug resistance, and interference with physiological processes pose significant challenges for the clinical translation of STAT3 inhibitors. This review provides insights into addressing these unresolved issues.