MCF7 cells were cultured in pH6.6 medium for 6/12/24h
Acidosis has been found to have multiple effects on tumor cells and immune cells among the tumor microenvironment. Ferroptosis is a nonapoptotic and iron-dependent form of cell death characterized by the accumulation of lipid peroxidation involved in various cancers. However, recent ferroptosis researches in the breast cancer (BC) acidic microenvironment context remains unrevealed. Acidosis induced ferroptosis in the ZFAND5/SLC3A2 independent manner to suppress tumor growth using in silico and multiple biological experiments. Mechanistically, we demonstrated that acidosis increased total/lipid ROS level, decreased GSH level and induced the morphological changes of mitochondria. Specifically, acidosis restrained the protein stability of SLC3A2 by promoting its ubiquitination process. Furthermore, acidosis combined with metformin or macrophages, could work in a synergistic manner to suppress the proliferation and enhance the ferroptosis of BC cells. This study firstly demonstrated that the ability of combination of acidosis and metformin, macrophages to induce ferroptosis might be a novel mechanism underlying its anti-BC effect. Overall design: RNA-saq analysis of MCF7 cells cultured in pH6.6 medium for 6/12/24h