Figure 2.

Mechanisms of necroptosis. Death receptors (TNFR, TLR, and IFNR) bind to their corresponding ligands (as shown) and are activated to trigger necroptosis. Upon caspase-8 or cIAP depletion, they promote the assembly of the RIPK1–RIPK3–MLKL signaling complex, resulting in the phosphorylation of MLKL (p-MLKL). Phosphorylated MLKL translocates to the plasma membrane to initiate membrane damage and form macropores. Ultimately, MLKL pores lead to necroptosis by allowing ion influx, cell swelling, membrane lysis, and subsequent uncontrolled release of intracellular substances. Due to membrane damage, potassium efflux can further activate NLRP3 through NEK7, increasing the release of inflammatory mediators. Recent studies have also found inhibitory factors of necroptosis, such as Nec-1 and SMYD2.