Synergistic induction of ferroptosis by paclitaxel and sunitinib is mediated through SLC7A11 in lung cancer.

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.