Cold atmospheric plasma potentiates ferroptosis via EGFR(Y1068)-mediated dual axes on GPX4 among triple negative breast cancer cells

Cold atmospheric plasma (CAP) has been proposed as an emerging onco-therapeutics that can specifically kill cancer cells without harming healthy cells. Here we explore its potency in triggering ferroptosis in transformed cells using triple negative breast cancer as the disease model. Through the whole transcriptome sequencing, mass spectrometry analysis, point mutation, and a series of <i>in vitro</i> and <i>in vivo</i> molecular assays, we identified two signaling axes centered at EGFR(Y1068), i.e., EGFR-TRIM25-KEAP1/SIAH2-NRF2 and EGFR-p38-NRF2, which suppressed GPX4 at both transcriptional and translational levels. We, in addition, demonstrated the potency of CAP in synergizing with Sorafenib towards enhanced selectivity against cancer cells via initiating ferroptosis. We are the first to systematically clarify the molecular mechanism of GPX4-dependent ferroptosis induced by CAP, and propose the feasibility of activating EGFR instead of suppressing it as well as the benefits of resolving tumors by coupling CAP with ferroptosis-inducing agents. The identified signaling axis is applicable to all cancers harboring EGFR that deserve intensive investigations.