<p>Ferroptosis is a non-apoptotic form of cell death that offers unique advantages in various cancer therapies. Gene therapy, on the other hand, involves transferring therapeutic genes into cancer cells to regulate related proteins and exert therapeutic effects. Nanomaterials that combine the ability to induce ferroptosis in cancer cells with gene delivery functionality hold great potential for tumor therapy. Herein, we designed and synthesized a series of ferrocene-containing (Fc) cationic lipids (NFC-1~4) based on the Ugi reaction. Fc, as a typical Fenton reaction catalyst, can effectively trigger ferroptosis in cancer cells. The results showed that NFC-1~3 lipoplexes could be efficiently taken up by A549 cells and exhibit excellent gene transfection capabilities, with the best transfection efficiency surpassing that of Lipofectamine 2000. Reactive oxygen species (ROS) detection experiments revealed that NFC-2 possesses Fenton characteristics, enabling it to induce the Fenton reaction and produce ROS. <i>In vitro</i> antitumor experiments demonstrated that NFC-2 LNPs could inhibit tumor cell growth to some extent, with its efficacy significantly enhanced after DNA encapsulation. Mechanistic studies indicated that the Fenton reaction mediated by NFC-2@DNA lipoplexes converted endogenous H₂O₂ into highly toxic ·OH, leading to increased intracellular ROS levels, glutathione (GSH) depletion, and inactivation of glutathione peroxidase 4 (GPX4). The disruption of the cellular redox balance caused excessive accumulation of lipid peroxides (LPOs), ultimately inducing ferroptosis. NFC-2 holds promise as an efficient ferroptosis agent and a dual-function lipid for co-delivering DNA, offering potential for combined gene therapy and ferroptosis-based cancer treatment.</p> Graphical abstract <p></p>