ATF3 Potentiates APR-246-Induced Ferroptosis in Sarcoma by Repressing SLC7A11 Expression

APR-246 (Eprenetapopt) is a clinical-stage small molecule compound, while recent studies suggest its potential involvement in ferroptosis, the precise mechanism and its effects in sarcomas remain unclear. This investigation constitutes the first endeavor to confirm in sarcoma cells that APR-246 induces ferroptosis in a dose-responsive manner, characterized by elevated reactive oxygen species and lipid peroxidation, depletion of glutathione, and mitochondrial shrinkage. Furthermore, this effect can be reversed by ferroptosis inhibitors rather than apoptosis inhibitors. More importantly, This study uncovers that the transcription factor ATF3 serves a pivotal function as a sensitizer for APR-246-induced ferroptosis. Transcriptomic analysis reveals ATF3 as one of the most prominently upregulated genes post-APR-246 treatment. Functionally, ATF3 overexpression significantly lowers the half-maximal inhibitory concentration of APR-246, intensifying ferroptosis-related biochemical and ultrastructural impairments. Mechanistically, ATF3 inhibits the expression of SLC7A11 directly, impeding the compensatory antioxidant response induced by APR-246. Within the nude mouse xenograft models, ATF3 overexpression combined with APR-246 markedly boosts the anti-tumor efficacy without notable toxicity. Consequently, this investigation clarifies the anti-tumor mechanism of APR-246 in sarcomas via ferroptosis and proposes, for the first time, that the ATF3-SLC7A11 axis can serve as an intervention target to enhance its ferroptosis efficacy.