Inhibition of LSD1 induces ferroptosis through the ATF4-xCT pathway and shows enhanced anti-tumor effects with ferroptosis inducers in NSCLC.

Lysine-specific demethylase 1 (LSD1) has been identified as an important epigenetic target, and recent advances in lung cancer therapy have highlighted the importance of targeting ferroptosis. However, the precise mechanisms by which LSD1 regulates ferroptosis remain elusive. In this study, we report that the inhibition of LSD1 induces ferroptosis by enhancing lipid peroxidation and reactive oxygen species (ROS) accumulation. Mechanistically, LSD1 inhibition downregulates the expression of activating transcription factor 4 (ATF4) through epigenetic modification of histone H3 lysine 9 dimethyl (H3K9me2), which sequentially inhibits the expression of the cystine-glutamate antiporter (xCT) and decreases glutathione (GSH) production. Furthermore, LSD1 inhibition transcriptionally upregulates the expression of transferrin receptor (TFRC) and acyl-CoA synthetase long chain family member 4 (ACSL4) by enhancing the binding of histone H3 lysine 4 dimethyl (H3K4me2) to their promoter sequences. Importantly, the combination of an LSD1 inhibitor and a ferroptosis inducer demonstrates an enhanced anti-tumor effect in a xenograft model of non-small cell lung cancer (NSCLC), surpassing the efficacy of either agent alone. These findings reveal new insights into the mechanisms by which LSD1 inhibition induces ferroptosis, offering potential guidance for the development of new strategies in the treatment of NSCLC.