Small-Molecule Inhibitors of Necroptosis: Current Status and Perspectives

Necroptosis, an important form of programmed cell death (PCD), is a highly regulated caspase-independent type of cell death that plays a critical role in the pathophysiology of various inflammatory, infectious, and degenerative diseases. Currently, receptor-interacting protein kinase 1 (RIPK1), RIPK3, and mixed lineage kinase domain-like protein (MLKL) have been widely recognized as critical therapeutic targets of the necroptotic machinery. Targeting RIPK1, RIPK3, and/or MLKL is a promising strategy for necroptosis-related diseases. Following the identification of the first RIPK1 inhibitor Nec-1 in 2005, the antinecroptosis field is attracting increasing research interest from multiple disciplines, including the biological and medicinal chemistry communities. Herein, we will review the functions of necroptosis in human diseases, as well as the related targets and representative small-molecule inhibitors, mainly focusing on research articles published during the past 10 years. Outlooks and perspectives on the associated challenges are also discussed.