Synergistic induction of ferroptosis by paclitaxel and sunitinib is mediated through SLC7A11 in lung cancer
- Int Immunopharmacol. 2026 Jun 15:179:116595. doi: 10.1016/j.intimp.2026.116595.
- 1. Core Laboratory, Tianjin Beichen Hospital, Tianjin 300400, China.
- 2. Department of Ultrasound, Tianjin Beichen Hospital, Tianjin 300400, China.
- 3. Department of Neurosurgery, Tianjin Beichen Hospital, Tianjin 300400, China.
- 4. Department of Pathology, Tianjin Beichen Hospital, Tianjin 300400, China.
- 5. Department of Pulmonary Medicine, Tianjin Beichen Hospital, Tianjin 300400, China.
- 6. Department of Cardiology, Tianjin Beichen Hospital, Tianjin 300400, China.
- 7. Core Laboratory, Tianjin Beichen Hospital, Tianjin 300400, China; Department of Critical Care Medicine, Core Laboratory, Tianjin Beichen Hospital, Tianjin, China. Electronic address: [email protected].
- 8. Medical Clinical Lab, Hospital of Renmin University of China, Beijing 100872, China. Electronic address: [email protected].
The combination of paclitaxel (PTX) and sunitinib (SUN) exhibits synergistic antitumor activity against lung Cancer, but the underlying mechanism is unclear. We show that PTX and SUN co-treatment synergistically inhibits tumor growth in murine allograft models and induces Ferroptosis in lung Cancer cells. Mechanistically, the combination concurrently downregulates Ferroptosis suppressors (FTH1, GPX4, SLC7A11) and upregulates the pro-ferroptotic enzyme ACSL4, leading to iron accumulation, glutathione depletion, and lethal lipid peroxidation. Genetic studies identify SLC7A11 as a critical mediator: its knockdown sensitizes cells to the combination, while its overexpression confers resistance. These findings establish a novel ferroptosis-based mechanism for the PTX/SUN synergy, positioning SLC7A11 as a key determinant of therapeutic response and providing a rationale for targeting this pathway in lung Cancer.