Advances in MLKL-targeted inhibitors and PROTACs for necroptosis therapeutics

Necroptosis is a highly regulated form of cell death. Mixed lineage kinase domain-like protein (MLKL) serves as its central effector and plays a critical role in various physiological and pathological processes. Given its close association with multiple diseases, MLKL has emerged as a promising therapeutic target. This review highlights recent advances in the development of necroptosis inhibitors and degraders targeting MLKL. The optimization of active compounds, structural modifications, and the applications of proteolysis-targeting chimeras (PROTACs) are emphasized. Furthermore, this study systematically evaluates the structural characteristics and biological activities of these compounds, thereby providing critical insights to inform future investigations and pharmaceutical development within this field.