Specifically, we found that (i) high-dose NMN (100 mM) suppressed lung adenocarcinoma A549 and SPCA1 cell proliferation and promoted cell death, whereas low-dose (10 mM) treatment produced the opposite effect; (ii) the cell death induced by high-dose NMN occurred through ferroptosis; (iii) high-dose NMN treatment mainly induced intracellular NAM overload to trigger ferroptotic cell death; and (iiii) high-dose NMN induced tumor ferroptosis through an overload-NAM-mediated SIRT1–AMPK–ACC pathway. Here, ATP2C1 is linked to neoplasm.