<p>Ferroptosis is a prospective approach for cancer treatment. However, the efficacy of ferroptosis therapy is limited by three parallel ferroptosis defense pathways: the glutathione (GSH)-glutathione peroxidase 4 (GPX4) pathway, the ferroptosis suppressor protein 1 (FSP1)-ubiquinol (CoQH2) pathway, and the dihydroorotate dehydrogenase (DHODH)-CoQH2 pathway. Inspired by the principles of preprogrammed chemical reaction networks (CRNs), herein, a novel drug delivery system (SRF@Au@M NPs) was designed based on MIL-100(Fe) for predictable behaviors in tumor cells to break the three ferroptosis defense systems. SRF@Au@M NPs were fabricated through the size optimization of MIL-100(Fe), sorafenib (SRF) loading, in-situ growth of Au nanoparticles (Au NPs) and surface modification with dihydrolipoic acid derivatives. SRF@Au@M NPs disintegrate in the presence of high concentrations of GSH, releasing sorafenib (SRF) into tumor cells, which reduces GSH synthesis and inhibits GPX4 activity. The Au nanoparticles decompose glucose to produce H₂O₂, providing fuel for the Fenton reaction and disrupting carbohydrate metabolism to inhibit NAD(P)H generation. Particularly, a novel redox-CRN was formed between dihydrolipoic acid derivatives and iron ions, continuously promoting reactive oxygen species generation while concurrently consume NADH. The imbalance of NAD(P)H metabolic homeostasis impedes the recycling of CoQ to CoQH2, resulting in the simultaneous inhibition of the FSP1-CoQH2 and DHODH-CoQH2 pathways. Consequently, the SRF@Au@M NPs triggered a potent ferroptosis storm in 4T1 tumor cells and achieved an 92.5% tumor growth inhibition in tumor-bearing mice, significantly higher than that of other treatment groups. Our sophisticated strategy based on CRNs provides a new promising paradigm for ferroptosis activation and cancer treatment.</p> Graphical Abstract <p></p>