Fig. 3.

TNF-α/TNFR1-induced necroptosis signaling pathway. The molecular mechanism of necroptosis is illustrated in the diagram, a controlled inflammatory cell death process distinct from apoptosis. Upon binding of TNF-α to its receptor TNFR1, Complex I form on the plasma membrane consisting of TRADD, TRAF2/5, RIPK1, and cIAPs, which ubiquitinate RIPK1 to facilitate cell survival signaling. Deubiquitination of RIPK1 triggers FADD and caspase-8 recruitment to form Complex II. When the function of caspase-8 is inhibited, RIPK1 interacts with RIPK3 through RHIM domains to form the necrosome. Inside the necrosome, RIPK1 and RIPK3 phosphorylate one another, activating phosphorylation of mixed lineage kinase domain-like protein (MLKL). p-MLKL moves towards the plasma membrane and interacts with phosphatidylinositol phosphates (PIPs), disrupting membrane integrity and causing osmotic disruption, swelling, and cell bursting, which are characteristics of necroptosis. This route focuses on the central role of RIPK1, RIPK3, and MLKL in necroptosis mediating inflammatory and reproductive pathologies