Fig. 2

The cross talk between pyroptosis and apoptosis or necroptosis. a–b Interplay between necroptosis and pyroptosis. MLKL is the terminal executioner of necroptosis, which is also a key intermedium between necroptosis and pyroptosis. RIPK1-RIPK3 association or cytosolic ZBP1 activation results in phosphorylation of MLKL, thus forming pores on the membrane and engaging necroptosis. Plasma and K⁺ efflux mediated by MLKL can ultimately lead to cellular stress, triggering NLRP3 activation, inflammasome assembly, and caspase-1 cleavage, which is the canonical pyroptosis pathway. ZBP1 can directly activate NLRP3 inflammasome in response to virus infection. Additionally, when TNF binding to TNFR on the cell membrane, complex I is assembled and activated, further forming ripoptosome complex. Caspase-8 from ripoptosome complex can in turn promote the initiation of caspase-3 and -7 to execute GSDME-mediated pyroptosis. b–c Interplay between pyroptosis and apoptosis. Caspase family of proteases and its targeting downstream molecules connect apoptosis with pyroptosis. In extrinsic apoptosis, recruitment of FADD and caspase-8 promotes the initiation of the death-inducing signaling complex (DISC) when death receptor is activated. Then, activated caspase-8 from DISC can promote the initiation of caspase-3 and -7 and execute GSDME-mediated pyroptosis. In intrinsic apoptosis, Bcl-2 family member Bid can be cleaved by caspase-8 and pyroptosis-inducing caspase-1 into proapoptotic tBID, together with intracellular stress, mitochondrial outer membrane permeabilization (MOMP) is induced, subsequently triggering cytochrome c release, apoptosome formation and caspase-9 activation, which in turn promotes activation of caspase-3 and -7