Dimethylmalonate induces ferroptosis by inhibiting the SUCNR1/PI3K/HIF-1α/SLC7A11 signaling axis in triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer characterized by the absence of the estrogen receptor (ER), progesterone receptor (PR), and HER2 protein, resulting in limited treatment options and a poor prognosis. In recent years, ferroptosis, a newly discovered form of programmed cell death, along with its key regulatory molecules, has emerged as a promising target for cancer treatment. Dimethyl malonate (DMM) is commonly used in studies of neurological disorders and oxidative stress-related diseases, but its application in the treatment of breast cancer, including TNBC, has not been explored. This study revealed that DMM significantly inhibits the proliferation and migration of TNBC cells. The underlying mechanism may involve disruption of the antioxidant defense system in TNBC cells, thereby promoting lipid peroxidation-induced ferroptosis. Furthermore, a zebrafish embryo coculture model confirmed the inhibitory effect of DMM on TNBC cell proliferation and migration in vivo, demonstrating its antitumor potential. At the molecular level, Western blotting, immunofluorescence, and qPCR confirmed that DMM inhibits the downstream PI3K/HIF-1α pathway mediated by the succinate receptor SUCNR1, thereby inhibiting the expression of the antioxidant molecules SLC7A11 and GPX4. This leads to the induction of ferroptosis, which suppresses TNBC cell proliferation and migration. Finally, overexpression experiments further validated the core regulatory role of SUCNR1 in this process.

This study reveals the molecular mechanism by which DMM induces ferroptosis in TNBC cells through the SUCNR1/PI3K/HIF-1α signaling pathway, providing new theoretical insights for the exploration of TNBC pathogenesis and clinical treatment strategies.