摘要：SummaryFerroptosis is a new kind of regulated cell death that is characterized by highly iron-dependent lipid peroxidation. Cancer cells differ in their sensitivity to ferroptosis. Here we showed that the Suppressor of fused homolog (SUFU), a critical component in Hedgehog signaling, regulates ferroptosis sensitivity of breast cancer cells. Ectopic SUFU expression suppressed, whereas depletion of SUFU enhanced the sensitivity of breast cancer cells to RSL3-triggered ferroptosis through deregulation of ACSL4. Moreover, SUFU depletion promoted the activation of Yes-associated protein (YAP), thereby increasing the expression of ACSL4. Mechanistically, SUFU is associated with LATS1. Deletion of a region comprising residues 174–385 in SUFU disrupted SUFU binding to LATS1, thus abrogating SUFU-mediated downregulation of the YAP-ACSL4 axis and sensitivity to ferroptosis. Noteworthy, we showed that vincristine downregulated SUFU, thus increasing breast cancer cell sensitivity to RSL3in vitroandin vivo. Together, our findings uncover SUFU as a novel regulator in ferroptosis sensitivity.Graphical abstractDisplay OmittedHighlights•SUFU regulates the sensitivity of breast cancer cells to ferroptosis•SUFU associates with LATS1 to downregulate the YAP-ACSL4 axis•Vincristine targets the SUFU-YAP-ACSL4 axisCell biology; Functional aspects of cell biology; Cancer
