Aspirin promotes ferroptosis by attenuating Nrf2 in triple-negative breast cancer

Abstract Purpose Recent research has found that patients who receive aspirin might have a reduced risk of breast cancer. However, how aspirin influences cancer remains controversial. Ferroptosis is an iron- and reactive oxygen species (ROS)-dependent form of regulated cell death (RCD), and it is crucial for the suppression of tumors. Herein, we investigated the mechanism of aspirin as a novel ferroptosis inducer in the antitumor effect of triple-negative breast cancer (TNBC). Methods We performed cell proliferation, ferroptosis-related and xenograft assays to determine the function and mechanism of aspirin in TNBC. Additionally, we investigated the transcriptomic profiles in TNBC tissues and normal tissues by RNA-seq. Results Our present study revealed that aspirin not only significantly accelerated ferroptosis but also inhibited the growth of TNBC cells. Intriguingly, aspirin, similar to the ferroptosis activator erastin, promoted ferroptosis and inhibited cell proliferation; however, the additional ferroptosis suppressor ferrostatin reversed the function of aspirin in ferroptosis and cell proliferation. Mechanistically, these results indicated that aspirin attenuated the level of Nrf2 protein and enhanced Keap1, mainly through the Keap1-Nrf2 pathway, in TNBC cells. Meanwhile, aspirin could also suppress key ferroptosis factors, such as GPX4 and xCT. Importantly, restoring Nrf2 signaling reversed aspirin-mediated ferroptosis. Furthermore, we found that oxidative stress and the Keap1-Nrf2 pathway were significantly changed. Conclusion Overall, our research demonstrates a novel role of aspirin in inhibiting Keap1-Nrf2 signaling to accelerate ferroptosis, which leads to the inhibition of cell proliferation in TNBC. Aspirin may present as a potential preventive strategy against the development of TNBC.