This study introduces synthetic protein circuits, termed "synpoptosis," that enable programmable control of cell death programs in mammalian cells. The circuits are designed to mimic natural cell death pathways, such as apoptosis and pyroptosis, and can be activated by specific proteases. Key features of the synpoptosis circuits include: 1. **Bidirectional Control**: The circuits can activate both apoptosis and pyroptosis, allowing for the induction of either mode of cell death. 2. **Combinatorial Logic**: The circuits can respond to combinations of protease inputs, enabling targeted cell death in specific cell populations. 3. **Targeted Elimination**: The circuits can selectively eliminate harmful cells while sparing healthy ones by interfacing with endogenous intracellular signals. 4. **Intercellular Transmission**: The circuits can be transmitted between cells, potentially enabling the engineering of synthetic killer cells that eliminate target cells without self-destruction. The study demonstrates that synpoptosis circuits can induce canonical features of cell death, such as morphological changes and the release of pro-inflammatory cytokines. These circuits also show promise for therapeutic applications, such as inducing cancer cell death in tumors or eliminating senescent cells. The research highlights the potential of synpoptosis circuits in addressing therapeutic challenges by providing active control over cell death modes.This study introduces synthetic protein circuits, termed "synpoptosis," that enable programmable control of cell death programs in mammalian cells. The circuits are designed to mimic natural cell death pathways, such as apoptosis and pyroptosis, and can be activated by specific proteases. Key features of the synpoptosis circuits include: 1. **Bidirectional Control**: The circuits can activate both apoptosis and pyroptosis, allowing for the induction of either mode of cell death. 2. **Combinatorial Logic**: The circuits can respond to combinations of protease inputs, enabling targeted cell death in specific cell populations. 3. **Targeted Elimination**: The circuits can selectively eliminate harmful cells while sparing healthy ones by interfacing with endogenous intracellular signals. 4. **Intercellular Transmission**: The circuits can be transmitted between cells, potentially enabling the engineering of synthetic killer cells that eliminate target cells without self-destruction. The study demonstrates that synpoptosis circuits can induce canonical features of cell death, such as morphological changes and the release of pro-inflammatory cytokines. These circuits also show promise for therapeutic applications, such as inducing cancer cell death in tumors or eliminating senescent cells. The research highlights the potential of synpoptosis circuits in addressing therapeutic challenges by providing active control over cell death modes.