Necroptosis is a form of regulated cell death (RCD) that evolved as a defence against pathogenic infection. Unlike caspase-dependent RCD, necroptosis, in its canonical form, is driven by receptor-interacting protein kinase 1 and 3 (RIPK1 and RIPK3) signalling, culminating in the activation of the pseudokinase mixed lineage kinase domain-like protein (MLKL). Central to this process is the interaction between MLKL and its upstream regulator, RIPK3, forming a functional module called the necrosome that governs the spatiotemporal execution of cell death. Despite progress in our understanding of necroptotic signalling, key open questions remain. The structural organization of MLKL influences its interaction with RIPK3, yet the precise features of their binding surfaces and their regulation are not fully resolved. Additionally, the high-order supramolecular assembly of the necrosome and its transition between different states remain poorly understood, particularly regarding how RIPK3 and MLKL configurations impact necrosome activity and stability. In this review, we summarize current knowledge on the evolution, structure and regulation of the RIPK3-MLKL axis and discuss models of their activation in light of recent discoveries.
Martínez-Osorio et al. (2026) studied this question.