[1][2] The assembly of the PANoptosome cell death complex occurs in response to germline-encoded pattern-recognition receptors (PRRs) sensing pathogens, including bacterial, viral, and fungal infections, as well as pathogen-associated molecular patterns, damage-associated molecular patterns, and cytokines that are released during infections, inflammatory conditions, and cancer.
[2] Inflammasome-dependent pyroptosis involves inflammatory caspases, including caspase-1 and caspase-11 in mice, and caspases-1, -4, and -5 in humans, and is executed by gasdermin D.[24][25][26][27][28][29][30] In contrast, necroptosis occurs via RIPK1/3-mediated MLKL activation, which is downstream of caspase-8 inhibition.
Additionally, activation of PANoptosis can clear infected cells for host defense, and it has shown preclinical promise as an anti-cancer strategy.
This suggests that inhibiting ZBP1 may improve the therapeutic efficacy of IFN therapy during SARS-CoV-2 infection and possibly other inflammatory conditions where IFN-mediated cell death and pathology occur.
[5][7][17][19] PANoptosis has also been observed in Salmonella enterica and Listeria monocytogenes infections, where the combined loss of caspases and RIPK3 significantly protects cells from death.
[58] Treatment of cancer cells with the PANoptosis-inducing agents TNF and IFN-γ[59][6] can reduce tumor size in preclinical models.