Figure 3.

Mechanistic pathways and regulatory targets of necroptosis. Upon activation of TNFR1, a complex I is formed consisting of TRADD, TRAF2/5, cIAP1/2, and RIPK1. cIAP1/2 ubiquitinates RIPK1, thereby inhibiting its activation. When caspase-8 and IAP activity are suppressed, RIPK1 is activated and forms complex II with FADD and caspase-8, which further activates RIPK3. The activated RIPK1-RIPK3 complex forms the necrosome, leading to the activation of MLKL and inducing necroptosis, accompanied by the release of DAMPs such as ATP and HMGB1.