Tiliroside induces ferroptosis to repress the development of triple-negative breast cancer cells.

Ferroptosis is a newly found form of non-apoptotic regulated cell death that is essential for the advancement of cancer. Tiliroside (Til), an effective natural flavonoid glycoside of oriental paperbush flower, has been explored as a potential anticancer agent in a few cancer types. However, it is unclear whether and how Til could promote the death of triple-negative breast cancer (TNBC) cells by inducing ferroptosis. Our study determined that Til induced cell death and attenuated cell proliferation in TNBC cells in vitro and in vivo with less toxicity for the first time. Functional assays showed that ferroptosis was the predominant form that contributed to Til-induced cell death of TNBC. Mechanistically, Til induces ferroptosis of TNBC cells via independent PUFA-PLS pathways but is closely involved in the Nrf2/HO-1 pathway. Silencing of HO-1 substantially abrogated the tumor-inhibiting effects of Til. In conclusion, our findings suggest that the natural product Til exerted its antitumor activity on TNBC by promoting ferroptosis, and the HO-1/SLC7A11 pathway plays an indispensable role in Til-induced ferroptotic cell death.