Activation of pathways controlled by the tumor‐suppressor protein p53 following oxidative stress or exposure to toxic chemicals is tightly associated with ferroptosis and cell death.[55] Using TRX conditional knockout mice, we demonstrated previously that TRX regulates HSPCs through p53.[56] In the current study, ORP100S was found to downregulate p53 and inhibit 5‐FU‐ and cisplatin‐induced p53‐MDM2‐ASPP1‐p21 signaling as well as ferroptosis in EML cells (Figure 3C), but not in cancer cells (Figure S6, Supporting Information). This evidence concerns the gene MDM2 and cancer.