FDX1-short proteoform induces caspase-independent cell death in tumor cells.

Cell death is a crucial process for the maintenance of physiological functions in organisms. In recent years, cuproptosis, a novel form of cell death induced by copper overload in mitochondria, has emerged as a critical regulatory mechanism. Ferredoxin 1 (FDX1), a key electron transfer protein in this pathway, is essential for copper metabolism and the regulation of cuproptosis. In this study, we characterized a natural short proteoform of FDX1, FDX1-Short Proteoform (FDX1-SP). Lacking the canonical N-terminal mitochondrial targeting sequence, FDX1-SP is widely distributed throughout the cell, with a pronounced propensity for nuclear accumulation. The accumulation of FDX1-SP protein triggers cleavage and degradation of tumor cell DNA. This disrupts nuclear membrane integrity and induces cell death in a caspase-independent manner. FDX1-SP preferentially damages highly accessible chromatin regions in tumor cells, thereby inducing tumor cell death. Based on these findings, we developed an FDX1-SP mRNA therapeutic, which exhibited significant DNA damage and anti-tumor effects in patient-derived xenograft (PDX) models. Our research uncovers the mechanism of death mediated by FDX1-SP, providing new directions for tumor therapy.