Simple SummaryFor multicellular organisms, cell death is a vital process, which ultimately leads to the destruction of unneeded cells. Proteases are key enzymes that play a vital role in breaking down proteins and maintaining an optimal environment in the cell. During key stages of some types of cell death, the nucleus plays a critical role, and the activity of nuclear proteins determines the fate of the cell. Regulation of these proteins is crucial in determining whether the cell proceeds towards cell death or not. This review aims to provide a comprehensive picture of nuclear proteases that regulate and potentially participate in various types of cell death via the destruction of nuclear proteins.AbstractMultiple factors can trigger cell death via various pathways, and nuclear proteases have emerged as essential regulators of these processes. While certain nuclear proteases have been extensively studied and their mechanisms of action are well understood, others remain poorly characterized. Regulation of nuclear protease activity is a promising therapeutic strategy that could selectively induce favorable cell death pathways in specific tissues or organs. Thus, by understanding the roles of newly discovered or predicted nuclear proteases in cell death processes, we can identify new pharmacological targets for improving therapeutic outcomes. In this article, we delved into the role of nuclear proteases in several types of cell death and explore potential avenues for future research and therapeutic development.