Fig. 18. Overview of PANoptosis.

PANoptosis is triggered by the formation of a protein complex called the PANoptosome, which includes several protein domains, namely, RIPK1, RIPK3, caspase-8, NLRP3, and ASC. This complex activates multiple types of cell death, including pyroptosis, apoptosis, and necroptosis, resulting in an inflammatory cell death response. During influenza A virus (IAV) infection, Z-DNA-binding protein (ZBP1) recognizes viral ribonucleoproteins and induces the formation of the ZBP1-dependent PANoptosome. TGF-β-activated kinase 1 (TAK1) is a crucial regulator of PANoptosis that negatively controls this process; however, bacterial infections can interrupt its suppression. Inhibition of TAK1 and activation of signaling through TLRs or death receptors promotes the formation of RIPK1-dependent PANoptosomes. During PANoptosis, the activation of caspase-1 or caspase-8 leads to the cleavage and activation of downstream effector proteins, such as gasdermin D and RIPK3, which drive pyroptosis and necroptosis, respectively. Activated caspase-8 subsequently cleaves and activates caspase-3, resulting in cell apoptosis.